Contributions to Mediation Analysis and First Principles Modeling for Mechanistic Statistical Analysis

This thesis contains three projects that propose novel methods for studying mechanisms that explain statistical relationships. The ultimate goal of each of these methods is to help researchers describe how or why complex relationships between observed variables exist. The first project proposes and studies a method for recovering mediation structure in high dimensions. We take a dimension reduction approach that generalizes the ``product of coefficients'' concept for univariate mediation analysis through the optimization of a loss function. We devise an efficient algorithm for optimizing the product-of-coefficients inspired loss function. Through extensive simulation studies, we show that the method is capable of consistently identifying mediation structure. Finally, two case studies are presented that demonstrate how the method can be used to conduct multivariate mediation analysis. The second project uses tools from conditional inference to improve the calibration of tests of univariate mediation hypotheses. The key insight of the project is that the non-Euclidean geometry of the null parameter space causes the test statistic’s sampling distribution to depend on a nuisance parameter. After identifying a statistic that is both sufficient for the nuisance parameter and approximately ancillary for the parameter of interest, we derive the test statistic’s limiting conditional sampling distribution. We additionally develop a non-standard bootstrap procedure for calibration in finite samples. We demonstrate through simulation studies that improved evidence calibration leads to substantial power increases over existing methods. This project suggests that conditional inference might be a useful tool in evidence calibration for other non-standard or otherwise challenging problems. In the last project, we present a methodological contribution to a pharmaceutical science study of {em in vivo} ibuprofen pharmacokinetics. We demonstrate how model misspecification in a first-principles analysis can be addressed by augmenting the model to include a term corresponding to an omitted source of variation. In previously used first-principles models, gastric emptying, which is pulsatile and stochastic, is modeled as first-order diffusion for simplicity. However, analyses suggest that the actual gastric emptying process is expected to be a unimodal smooth function, with phase and amplitude varying by subject. Therefore, we adopt a flexible approach in which a highly idealized parametric version of gastric emptying is combined with a Gaussian process to capture deviations from the idealized form. These functions are characterized by their distributions, which allows us to learn their common and unique features across subjects despite that these features are not directly observed. Through simulation studies, we show that the proposed approach is able to identify certain features of latent function distributions.PHDStatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163026/1/josephdi_1.pd

Measuring the effects of α1 -antitrypsin polymerisation on the structure and biophysical properties of the endoplasmic reticulum.

An important function of the endoplasmic reticulum (ER) is to serve as a site of secretory protein folding. When the accumulation of misfolded proteins threatens to disturb luminal homoeostasis, the cell is said to experience ER stress. By contrast, the accumulation of well-folded proteins inside the ER leads to a distinct form of strain called ER overload. The serpins comprise a large family of proteins whose folding has been studied in great detail. Some mutant serpins misfold to cause ER stress, whereas others fold but then polymerise to cause ER overload. We discuss recent advances in the use of dynamic fluorescence imaging to study these phenomena. We also discuss a new technique that we recently published, rotor-based organelle viscosity imaging (ROVI), which promises to shed more light on the biophysical features of ER stress and ER overload

Primary care physicians are under-testing for celiac disease in patients with iron deficiency anemia: Results of a national survey

BACKGROUND: Iron deficiency anemia (IDA) is a common extra-intestinal manifestation of celiac disease (CD). Little is known about the frequency with which primary care physicians (PCPs) test for CD in patients with IDA. We aimed to describe how PCPs approach testing for CD in asymptomatic patients with IDA. METHODS: We electronically distributed a survey to PCPs who are members of the American College of Physicians. Respondents were asked whether they would test for CD (serologic testing, refer for esophagogastroduodenoscopy [EGD], or refer to GI) in hypothetical patients with new IDA, including: (1) a young Caucasian man, (2) a premenopausal Caucasian woman, (3) an elderly Caucasian man, and (4) a young African American man. These scenarios were chosen to assess for differences in testing for CD based on age, gender, and race. Multivariable logistic regression was used to identify independent predictors of testing. RESULTS: Testing for CD varied significantly according to patient characteristics, with young Caucasian men being the most frequently tested (61% of respondents reporting they would perform serologic testing in this subgroup (p CONCLUSIONS: PCPs are under-testing for CD in patients with IDA, regardless of age, gender, race, or post-menopausal status. The majority of PCPs surveyed reported they do not strictly adhere to established guidelines regarding a confirmatory duodenal biopsy in a patient with positive serology for CD

Properties of a Novel Ion-Exchange Film

A new ion-exchange material (based on polyacrylic acid) and some of its analytical applications have been reported. This paper contains data on the ion-exchange properties of the film form of the material and its potential application to the decontamination of waste water and drinking water. The film has a high exchange capacity of 5 to 6 meq/g and a pK(sub a) of 5.7. The calcium form is the most effective for removing metal ions from solution, and the optimum pH range is between 5 and 7. The exchange rates are slower for the film than for bead and powder forms of the ion-exchange material; otherwise, the properties are similar. The film is effective when hard water solutions are employed and also when metal ions are in the complex matrix of waste water from electroplating. The film can be used in flow systems having a flow channel large enough to allow passage of turbid solutions

Identification and Synthesis of a Male-Produced Pheromone for the Neotropical Root Weevil Diaprepes abbreviatus

An unsaturated hydroxy-ester pheromone was isolated from the headspace and feces of male Diaprepes abbreviatus, identified, and synthesized. The pheromone, methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate, was discovered by gas chromatography-coupled electroantennogram detection (GC-EAD), and identified by gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance spectroscopy (NMR). The synthesis yielded an 86:14 mixture of methyl (E)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate (active) and methyl (Z)-3-(2-hydroxyethyl)-4-methyl-2-pentenoate (inactive), along with a lactone breakdown product. The activity of the synthetic E-isomer was confirmed by GC-EAD, GC-MS, NMR, and bioassays. No antennal response was observed to the Z-isomer or the lactone. In a two-choice olfactometer bioassay, female D. abbreviatus moved upwind towards the synthetic pheromone or natural pheromone more often compared with clean air. Males showed no clear preference for the synthetic pheromone. This pheromone, alone or in combination with plant volatiles, may play a role in the location of males by female D. abbreviatus

The integrated stress response regulates BMP signalling through effects on translation.

BACKGROUND: Developmental pathways must be responsive to the environment. Phosphorylation of eIF2α enables a family of stress-sensing kinases to trigger the integrated stress response (ISR), which has pro-survival and developmental consequences. Bone morphogenetic proteins (BMPs) regulate multiple developmental processes in organisms from insects to mammals. RESULTS: Here we show in Drosophila that GCN2 antagonises BMP signalling through direct effects on translation and indirectly via the transcription factor crc (dATF4). Expression of a constitutively active GCN2 or loss of the eIF2α phosphatase dPPP1R15 impairs developmental BMP signalling in flies. In cells, inhibition of translation by GCN2 blocks downstream BMP signalling. Moreover, loss of d4E-BP, a target of crc, augments BMP signalling in vitro and rescues tissue development in vivo. CONCLUSION: These results identify a novel mechanism by which the ISR modulates BMP signalling during development

Chemosensory Responses to the Repellent Nepeta Essential Oil and Its Major Component Nepetalactone by Aedes aegypti (Diptera: Culicidae), a Vector of Zika Virus

Nepeta essential oil (Neo; catnip) and its major component, nepetalactone, have long been known to repel insects including mosquitoes. However, the neural mechanisms through which these repellents are detected by mosquitoes, including the yellow fever mosquito Aedes aegypti (L.), an important vector of Zika virus, were poorly understood. Here we show that Neo volatiles activate olfactory receptor neurons within the basiconic sensilla on the maxillary palps of female Ae. aegypti. A gustatory receptor neuron sensitive to the feeding deterrent quinine and housed within sensilla on the labella of females was activated by both Neo and nepetalactone. Activity of a second gustatory receptor neuron sensitive to the feeding stimulant sucrose was suppressed by both repellents. Our results provide neural pathways for the reported spatial repellency and feeding deterrence of these repell ents. A better understanding of the neural input through which female mosquitoes make decisions to feed will facilitate design of new repellents and management strategies involving their use.The final publication is now available at: [https://doi.org/10.1093/jme/tjx059

Membrane Proteins Mediating Reception and Transduction in Chemosensory Neurons in Mosquitoes

Mosquitoes use chemical cues to modulate important behaviors such as feeding, mating, and egg laying. The primary chemosensory organs comprising the paired antennae, maxillary palps and labial palps are adorned with porous sensilla that house primary sensory neurons. Dendrites of these neurons provide an interface between the chemical environment and higher order neuronal processing. Diverse proteins located on outer membranes interact with chemicals, ions, and soluble proteins outside the cell and within the lumen of sensilla. Here, we review the repertoire of chemosensory receptors and other membrane proteins involved in transduction and discuss the outlook for their functional characterization. We also provide a brief overview of select ion channels, their role in mammalian taste, and potential involvement in mosquito taste. These chemosensory proteins represent targets for the disruption of harmful biting behavior and disease transmission by mosquito vectors

Multimodal Stimulation of Colorado Potato Beetle Reveals Modulation of Pheromone Response by Yellow Light

Orientation of insects to host plants and conspecifics is the result of detection and integration of chemical and physical cues present in the environment. Sensory organs have evolved to be sensitive to important signals, providing neural input for higher order multimodal processing and behavioral output. Here we report experiments to determine decisions made by Colorado potato beetle (CPB), Leptinotarsa decemlineata, in response to isolated stimuli and multimodal combinations of signals on a locomotion compensator. Our results show that in complete darkness and in the absence of other stimuli, pheromonal stimulation increases attraction behavior of CPB as measured in oriented displacement and walking speed. However, orientation to the pheromone is abolished when presented with the alternative stimulation of a low intensity yellow light in a dark environment. The ability of the pheromone to stimulate these diurnal beetles in the dark in the absence of other stimuli is an unexpected but interesting observation. The predominance of the phototactic response over that to pheromone when low intensity lights were offered as choices seems to confirm the diurnal nature of the insect. The biological significance of the response to pheromone in the dark is unclear. The phototactic response will play a key role in elucidating multimodal stimulation in the host-finding process of CPB, and perhaps other insects. Such information might be exploited in the design of applications to attract and trap CPB for survey or control purposes and other insect pests using similar orientation mechanisms

Gas and gas hydrate distribution around seafloor seeps in Mississippi Canyon, Northern Gulf of Mexico, using multi-resolution seismic imagery

This paper is not subject to U.S. copyright. The definitive version was published in Marine and Petroleum Geology 25 (2008): 952-959, doi:10.1016/j.marpetgeo.2008.01.015.To determine the impact of seeps and focused flow on the occurrence of shallow gas hydrates, several seafloor mounds in the Atwater Valley lease area of the Gulf of Mexico were surveyed with a wide range of seismic frequencies. Seismic data were acquired with a deep-towed, Helmholz resonator source (220–820 Hz); a high-resolution, Generator-Injector air-gun (30–300 Hz); and an industrial air-gun array (10–130 Hz). Each showed a significantly different response in this weakly reflective, highly faulted area. Seismic modeling and observations of reversed-polarity reflections and small scale diffractions are consistent with a model of methane transport dominated regionally by diffusion but punctuated by intense upward advection responsible for the bathymetric mounds, as well as likely advection along pervasive filamentous fractures away from the mounds.This work was funded through ONR program element 61153N, and U.S. Department of Energy Grant DE-A126-97FT3423