Engineering topics

Bulla, Ingo

Publications and source records attributed to Bulla, Ingo.

6 records

DOE OSTI2018

Systematic evaluation of the population-level effects of alternative treatment strategies on the basic reproduction number

An approach to estimate the influence of the treatment-type controls on the basic reproduction number, R 0 , is proposed and elaborated. The presented approach allows one to estimate the effect of a given treatment strategy or to compare a number of different treatment strategies on the basic reproduction number. All our results are valid for sufficiently small values of the control. However, in many cases it is possible to extend this analysis to larger values of the control as was illustrated by examples.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Sensitivity of joint contagiousness and susceptibility-based dynamic optimal control strategies for HIV prevention

Predicting the population-level effects of an infectious disease intervention that incorporate multiple modes of intervention is complicated by the joint non-linear dynamics of both infection transmission and the intervention itself. In this paper, we consider the sensitivity of Dynamic Optimal Control Profiles (DOCPs) for the optimal joint investment in both a contagiousness and susceptibility-based control of HIV to bio-behavioral, economic, and programmatic assumptions. The DOCP is calculated using recently developed numerical algorithms that allow controls to be represented by a set of piecewise constant functions that maintain a constant yearly budget. Our transmission model assumes multiple stages of HIV infection corresponding to acute and chronic infection and both within- and between-individual behavioral heterogeneity. We parameterize a baseline scenario from a longitudinal study of sexual behavior in MSM and consider sensitivity of the DOCPs to deviations from that baseline scenario. In the baseline scenario, the primary determinant of the dominant control were programmatic factors, regardless of budget. In sensitivity analyses, the qualitative aspects of the optimal control policy were often robust to significant deviation in assumptions regarding transmission dynamics. In addition, we found several conditions in which long-term joint investment in both interventions was optimal. Our results suggest that modeling in the service of decision support for intervention design can improve population-level effects of a limited set of economic resources. We found that economic and programmatic factors were as important as the inherent transmission dynamics in determining population-level intervention effects. Given our finding that the DOCPs were robust to alternative biological and behavioral assumptions it may be possible to identify DOCPs even when the data are not sufficient to identify a transmission model.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2018

Notos - a galaxy tool to analyze CpN observed expected ratios for inferring DNA methylation types

Background: DNA methylation patterns store epigenetic information in the vast majority of eukaryotic species. The relatively high costs and technical challenges associated with the detection of DNA methylation however have created a bias in the number of methylation studies towards model organisms. Consequently, it remains challenging to infer kingdom-wide general rules about the functions and evolutionary conservation of DNA methylation. Methylated cytosine is often found in specific CpN dinucleotides, and the frequency distributions of, for instance, CpG observed/expected (CpG o/e) ratios have been used to infer DNA methylation types based on higher mutability of methylated CpG. Results: Predominantly model-based approaches essentially founded on mixtures of Gaussian distributions are currently used to investigate questions related to the number and position of modes of CpG o/e ratios. These approaches require the selection of an appropriate criterion for determining the best model and will fail if empirical distributions are complex or even merely moderately skewed. We use a kernel density estimation (KDE) based technique for robust and precise characterization of complex CpN o/e distributions without a priori assumptions about the underlying distributions. Conclusions: We show that KDE delivers robust descriptions of CpN o/e distributions. For straightforward processing, we have developed a Galaxy tool, called Notos and available at the ToolShed, that calculates these ratios of input FASTA files and fits a density to their empirical distribution. Based on the estimated density the number and shape of modes of the distribution is determined, providing a rational for the prediction of the number and the types of different methylation classes. Notos is written in R and Perl.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2017

Donor-Recipient Identification in Para- and Poly-phyletic Trees Under Alternative HIV-1 Transmission Hypotheses Using Approximate Bayesian Computation

Diversity of the founding population of Human Immunodeficiency Virus Type 1 (HIV-1) transmissions raises many important biological, clinical, and epidemiological issues. In up to 40% of sexual infections, there is clear evidence for multiple founding variants, which can influence the efficacy of putative prevention methods, and the reconstruction of epidemiologic histories. To infer who-infected-whom, and to compute the probability of alternative transmission scenarios while explicitly taking phylogenetic uncertainty into account, we created an approximate Bayesian computation (ABC) method based on a set of statistics measuring phylogenetic topology, branch lengths, and genetic diversity. We applied our method to a suspected heterosexual transmission case involving three individuals, showing a complex monophyletic-paraphyletic-polyphyletic phylogenetic topology. We detected that seven phylogenetic lineages had been transmitted between two of the individuals based on the available samples, implying that many more unsampled lineages had also been transmitted. Testing whether the lineages had been transmitted at one time or over some length of time suggested that an ongoing superinfection process over several years was most likely. While one individual was found unlinked to the other two, surprisingly, when evaluating two competing epidemiological priors, the donor of the two that did infect each other was not identified by the host root-label, and was also not the primary suspect in that transmission. This highlights that it is important to take epidemiological information into account when analyzing support for one transmission hypothesis over another, as results may be nonintuitive and sensitive to details about sampling dates relative to possible infection dates. Here, our study provides a formal inference framework to include information on infection and sampling times, and to investigate ancestral node-label states, transmission direction, transmitted genetic diversity, and frequency of transmission.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Exploration of Circadian Rhythms in Patients with Bilateral Vestibular Loss

Background New insights have expanded the influence of the vestibular system to the regulation of circadian rhythmicity. Indeed, hypergravity or bilateral vestibular loss (BVL) in rodents causes a disruption in their daily rhythmicity for several days. The vestibular system thus influences hypothalamic regulation of circadian rhythms on Earth, which raises the question of whether daily rhythms might be altered due to vestibular pathology in humans. The aim of this study was to evaluate human circadian rhythmicity in people presenting a total bilateral vestibular loss (BVL) in comparison with control participants. Methodology and Principal Findings Nine patients presenting a total idiopathic BVL and 8 healthy participants were compared. Their rest-activity cycle was recorded by actigraphy at home over 2 weeks. The daily rhythm of temperature was continuously recorded using a telemetric device and salivary cortisol was recorded every 3 hours from 6:00AM to 9:00PM over 24 hours. BVL patients displayed a similar rest activity cycle during the day to control participants but had higher nocturnal actigraphy, mainly during weekdays. Sleep efficiency was reduced in patients compared to control participants. Patients had a marked temperature rhythm but with a significant phase advance (73 min) and a higher variability of the acrophase (from 2:24 PM to 9:25 PM) with no correlation to rest-activity cycle, contrary to healthy participants. Salivary cortisol levels were higher in patients compared to healthy people at any time of day. Conclusion We observed a marked circadian rhythmicity of temperature in patients with BVL, probably due to the influence of the light dark cycle. However, the lack of synchronization between the temperature and rest-activity cycle supports the hypothesis that the vestibular inputs are salient input to the circadian clock that enhance the stabilization and precision of both external and internal entrainment.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2016

Phylogenetically resolving epidemiologic linkage

The use of phylogenetic trees in epidemiological investigations has become commonplace, but their epidemiological interpretation has not been systematically evaluated. Here, we use an HIV-1 within-host coalescent model to probabilistically evaluate transmission histories of two epidemiologically linked hosts. Previous critique of phylogenetic reconstruction has claimed that direction of transmission is difficult to infer, and that the existence of unsampled intermediary links or common sources can never be excluded. The phylogenetic relationship between the HIV populations of epidemiologically linked hosts can be classified into six types of trees, based on cladistic relationships and whether the reconstruction is consistent with the true transmission history or not. We show that the direction of transmission and whether unsampled intermediary links or common sources existed make very different predictions about expected phylogenetic relationships: (i) Direction of transmission can often be established when paraphyly exists, (ii) intermediary links can be excluded when multiple lineages were transmitted, and (iii) when the sampled individuals’ HIV populations both are monophyletic a common source was likely the origin. Inconsistent results, suggesting the wrong transmission direction, were generally rare. In addition, the expected tree topology also depends on the number of transmitted lineages, the sample size, the time of the sample relative to transmission, and how fast the diversity increases after infection. Typically, 20 or more sequences per subject give robust results. Moreover, we confirm our theoretical evaluations with analyses of real transmission histories and discuss how our findings should aid in interpreting phylogenetic results.

59 BASIC BIOLOGICAL SCIENCES↗