Population Physiology: Leveraging Electronic Health Record Data to Understand Human Endocrine Dynamics

Studying physiology and pathophysiology over a broad population for long periods of time is difficult primarily because collecting human physiologic data can be intrusive, dangerous, and expensive. One solution is to use data that have been collected for a different purpose. Electronic health record (EHR) data promise to support the development and testing of mechanistic physiologic models on diverse populations and allow correlation with clinical outcomes, but limitations in the data have thus far thwarted such use. For example, using uncontrolled population-scale EHR data to verify the outcome of time dependent behavior of mechanistic, constructive models can be difficult because: (i) aggregation of the population can obscure or generate a signal, (ii) there is often no control population with a well understood health state, and (iii) diversity in how the population is measured can make the data difficult to fit into conventional analysis techniques. This paper shows that it is possible to use EHR data to test a physiological model for a population and over long time scales. Specifically, a methodology is developed and demonstrated for testing a mechanistic, time-dependent, physiological model of serum glucose dynamics with uncontrolled, population-scale, physiological patient data extracted from an EHR repository. It is shown that there is no observable daily variation the normalized mean glucose for any EHR subpopulations. In contrast, a derived value, daily variation in nonlinear correlation quantified by the time-delayed mutual information (TDMI), did reveal the intuitively expected diurnal variation in glucose levels amongst a random population of humans. Moreover, in a population of continuously (tube) fed patients, there was no observable TDMI-based diurnal signal. These TDMI-based signals, via a glucose insulin model, were then connected with human feeding patterns. In particular, a constructive physiological model was shown to correctly predict the difference between the general uncontrolled population and a subpopulation whose feeding was controlled

Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study

In a randomized, placebo-controlled trial in Ghana, 67 onchocerciasis patients received 200-mg/day doxycycline for 4–6 weeks, followed by ivermectin (IVM) after 6 months. After 6–27 months, efficacy was evaluated by onchocercoma histology, PCR and microfilariae determination. Administration of doxycycline resulted in endobacteria depletion and female worm sterilization. The 6-week treatment was macrofilaricidal, with >60% of the female worms found dead, despite the presence of new, Wolbachia-containing worms acquired after the administration of doxycycline. Doxycycline may be developed as second-line drug for onchocerciasis, to be administered in areas without transmission, in foci with IVM resistance and in areas with Loa co-infections

A phase IIa clinical biomarker trial of aspirin and dietary arginine restriction in colorectal cancer patients.

TPS132 Background: Colorectal cancer (CRC) patients are at high risk for recurrence and for secondary CRC development. Our preliminary findings provide a rationale for reducing tissue polyamines as tertiary chemoprevention in local and locally-advanced CRC patients. We will attempt to demonstrate rectal tissue putrescine reduction in stage I-III, optimally-treated CRC patients after treatment with dietary arginine restriction + daily oral aspirin in a phase IIa clinical biomarker trial.24 participants will be treated with aspirin and an individualized dietary regimen to reduce arginine intake by >30% during the 12-week intervention. Sample size calculations were based on the Binomial test for a single proportion, to yield 80% Power. Six patients will receive psychosocial telephone counseling (PTC). Endoscopy with serial biopsies, phlebotomy, and urine collection will be performed pre- and post-intervention to assess potential biomarkers. The primary endpoint is a > 50% decrease in rectal tissue putrescine levels from baseline, as a measure of polyamine reduction in the target tissue of CRC patients. Secondary aims include: to demonstrate significant alterations in secondary endpoint biomarkers relevant to polyamine metabolism in CRC patients, including rectal mucosa Odc1 and Ssat expression and urinary polyamine metabolites; to determine this intervention's side-effect profile in a population of optimally-treated CRC patients; to determine the efficacy of accrual to this novel type of clinical trial involving dietary intervention and oral aspirin therapy among a group of potentially cured cancer patients for whom there is currently no recommended further therapy; to assess feasibility of PTC and collect pilot data regarding the influence of PTC on compliance with the dietary prescription and compliance with aspirin, and if PTC further influences healthy exercise, reduced fatigue and improved quality of life when compared to the non-counseled cohort.Among optimally-treated stage I-III CRC patients, a 12-week intervention of daily aspirin and a low-meat, arginine-restricted diet will favorably alter polyamine-related tissue, serum, and urinary biomarker levels

A phase IIa clinical biomarker trial of aspirin and dietary arginine restriction in colorectal cancer patients.

TPS132 Background: Colorectal cancer (CRC) patients are at high risk for recurrence and for secondary CRC development. Our preliminary findings provide a rationale for reducing tissue polyamines as tertiary chemoprevention in local and locally-advanced CRC patients. We will attempt to demonstrate rectal tissue putrescine reduction in stage I-III, optimally-treated CRC patients after treatment with dietary arginine restriction + daily oral aspirin in a phase IIa clinical biomarker trial.24 participants will be treated with aspirin and an individualized dietary regimen to reduce arginine intake by >30% during the 12-week intervention. Sample size calculations were based on the Binomial test for a single proportion, to yield 80% Power. Six patients will receive psychosocial telephone counseling (PTC). Endoscopy with serial biopsies, phlebotomy, and urine collection will be performed pre- and post-intervention to assess potential biomarkers. The primary endpoint is a > 50% decrease in rectal tissue putrescine levels from baseline, as a measure of polyamine reduction in the target tissue of CRC patients. Secondary aims include: to demonstrate significant alterations in secondary endpoint biomarkers relevant to polyamine metabolism in CRC patients, including rectal mucosa Odc1 and Ssat expression and urinary polyamine metabolites; to determine this intervention's side-effect profile in a population of optimally-treated CRC patients; to determine the efficacy of accrual to this novel type of clinical trial involving dietary intervention and oral aspirin therapy among a group of potentially cured cancer patients for whom there is currently no recommended further therapy; to assess feasibility of PTC and collect pilot data regarding the influence of PTC on compliance with the dietary prescription and compliance with aspirin, and if PTC further influences healthy exercise, reduced fatigue and improved quality of life when compared to the non-counseled cohort.Among optimally-treated stage I-III CRC patients, a 12-week intervention of daily aspirin and a low-meat, arginine-restricted diet will favorably alter polyamine-related tissue, serum, and urinary biomarker levels