Communicating regulatory high-throughput sequencing data using BioCompute Objects.

This project demonstrates the use of the IEEE 2791-2020 Standard (BioCompute Objects [BCO]) to enable the complete and concise communication of results from next generation sequencing (NGS) analysis. One arm of a clinical trial was replicated using synthetically generated data made to resemble real biological data and then two independent analyses were performed. The first simulated a pharmaceutical regulatory submission to the US Food and Drug Administration (FDA) including analysis of results and a BCO. The second simulated an FDA review that included an independent analysis of the submitted data. Of the 118 simulated patient samples generated, 117 (99.15%) were in agreement in the two analyses. This process exemplifies how a template BCO (tBCO), including a verification kit, facilitates transparency and reproducibility, thereby reinforcing confidence in the regulatory submission process.

Babesiosis Occurrence among the Elderly in the United States, as Recorded in Large Medicare Databases during 2006-2013.

BACKGROUND: Human babesiosis, caused by intraerythrocytic protozoan parasites, can be an asymptomatic or mild-to-severe disease that may be fatal. The study objective was to assess babesiosis occurrence among the U.S. elderly Medicare beneficiaries, ages 65 and older, during 2006-2013. METHODS: Our retrospective claims-based study utilized large Medicare administrative databases. Babesiosis occurrence was ascertained by recorded ICD-9-CM diagnosis code. The study assessed babesiosis occurrence rates (per 100,000 elderly Medicare beneficiaries) overall and by year, age, gender, race, state of residence, and diagnosis months. RESULTS: A total of 10,305 elderly Medicare beneficiaries had a recorded babesiosis diagnosis during the eight-year study period, for an overall rate of about 5 per 100,000 persons. Study results showed a significant increase in babesiosis occurrence over time (p<0.05), with the largest number of cases recorded in 2013 (N = 1,848) and the highest rates (per 100,000) in five Northeastern states: Connecticut (46), Massachusetts (45), Rhode Island (42), New York (27), and New Jersey (14). About 75% of all cases were diagnosed from May through October. Babesiosis occurrence was significantly higher among males vs. females and whites vs. non-whites. CONCLUSION: Our study reveals increasing babesiosis occurrence among the U.S. elderly during 2006-2013, with highest rates in the babesiosis-endemic states. The study also shows variation in babesiosis occurrence by age, gender, race, state of residence, and diagnosis months. Overall, our study highlights the importance of large administrative databases in assessing the occurrence of emerging infections in the United States.

A comparative pharmacokinetic estimate of mercury in U.S. Infants following yearly exposures to inactivated influenza vaccines containing thimerosal.

The use of thimerosal preservative in childhood vaccines has been largely eliminated over the past decade in the United States because vaccines have been reformulated in single-dose vials that do not require preservative. An exception is the inactivated influenza vaccines, which are formulated in both multidose vials requiring preservative and preservative-free single-dose vials. As part of an ongoing evaluation by USFDA of the safety of biologics throughout their lifecycle, the infant body burden of mercury following scheduled exposures to thimerosal preservative in inactivated influenza vaccines in the United States was estimated and compared to the infant body burden of mercury following daily exposures to dietary methylmercury at the reference dose established by the USEPA. Body burdens were estimated using kinetic parameters derived from experiments conducted in infant monkeys that were exposed episodically to thimerosal or MeHg at identical doses. We found that the body burden of mercury (AUC) in infants (including low birth weight) over the first 4.5 years of life following yearly exposures to thimerosal was two orders of magnitude lower than that estimated for exposures to the lowest regulatory threshold for MeHg over the same time period. In addition, peak body burdens of mercury following episodic exposures to thimerosal in this worst-case analysis did not exceed the corresponding safe body burden of mercury from methylmercury at any time, even for low-birth-weight infants. Our pharmacokinetic analysis supports the acknowledged safety of thimerosal when used as a preservative at current levels in certain multidose infant vaccines in the United States.

Babesiosis among elderly Medicare beneficiaries, United States, 2006-2008.

We used administrative databases to assess babesiosis among elderly persons in the United States by year, sex, age, race, state of residence, and diagnosis months during 2006-2008. The highest babesiosis rates were in Connecticut, Rhode Island, New York, and Massachusetts, and findings suggested babesiosis expansion to other states.

Updated aluminum pharmacokinetics following infant exposures through diet and vaccination.

Aluminum is a ubiquitous element that is released naturally into the environment via volcanic activity and the breakdown of rocks on the earth's surface. Exposure of the general population to aluminum occurs primarily through the consumption of food, antacids, and buffered analgesics. Exposure to aluminum in the general population can also occur through vaccination, since vaccines often contain aluminum salts (frequently aluminum hydroxide or aluminum phosphate) as adjuvants. Because concerns have been expressed by the public that aluminum in vaccines may pose a risk to infants, we developed an up-to-date analysis of the safety of aluminum adjuvants. Keith et al. [1] previously analyzed the pharmacokinetics of aluminum for infant dietary and vaccine exposures and compared the resulting body burdens to those based on the minimal risk levels (MRLs) established by the Agency for Toxic Substances and Disease Registry. We updated the analysis of Keith et al. [1] with a current pediatric vaccination schedule [2]; baseline aluminum levels at birth; an aluminum retention function that reflects changing glomerular filtration rates in infants; an adjustment for the kinetics of aluminum efflux at the site of injection; contemporaneous MRLs; and the most recent infant body weight data for children 0-60 months of age [3]. Using these updated parameters we found that the body burden of aluminum from vaccines and diet throughout an infant's first year of life is significantly less than the corresponding safe body burden of aluminum modeled using the regulatory MRL. We conclude that episodic exposures to vaccines that contain aluminum adjuvant continue to be extremely low risk to infants and that the benefits of using vaccines containing aluminum adjuvant outweigh any theoretical concerns.

Potential for internalization, growth, and survival of Salmonella and Escherichia coli O157:H7 in oranges.

Internalization potential, survival, and growth of human pathogens within oranges were investigated in a series of laboratory experiments. Submerging oranges into dye solutions at various temperature differentials was used to assess internalization potential. Conditions in which dye internalization was observed were further studied by applying Escherichia coli O157:H7 or Salmonella onto the stem scar, subjecting the oranges to a temperature differential, juicing, and measuring numbers of pathogens in the resulting juice. Pathogens for growth and survival studies were applied to or injected into simulated peel punctures. Oranges with small peel holes of selected sizes were also placed into solutions containing these pathogens. Bacterial survival was also evaluated in orange juice at 4 and 24 degrees C. Oranges internalized pathogens at a frequency of 2.5 to 3.0%, which mirrored dye internalization frequency (3.3%). Pathogens were internalized at an uptake level of 0.1 to 0.01% of the challenge applied. Bacteria grew within oranges at 24 degrees C, but not at 4 degrees C. Thirty-one percent of oranges with 0.91-mm surface holes showed pathogen uptake, whereas 2% of oranges with 0.68-mm holes showed pathogen uptake. Pathogens added to fresh orange juice and incubated at 24 degrees C declined 1 log CFU/ml within 3 days. These results suggest that internalization, survival, and growth of human bacterial pathogens can occur within oranges intended for producing unpasteurized juice.