Penalized mixed-effects ordinal response models for high-dimensional genomic data in twins and families

The Brisbane Longitudinal Twin Study (BLTS) was being conducted in Australia and was funded by the US National Institute on Drug Abuse (NIDA). Adolescent twins were sampled as a part of this study and surveyed about their substance use as part of the Pathways to Cannabis Use, Abuse and Dependence project. The methods developed in this dissertation were designed for the purpose of analyzing a subset of the Pathways data that includes demographics, cannabis use metrics, personality measures, and imputed genotypes (SNPs) for 493 complete twin pairs (986 subjects.) The primary goal was to determine what combination of SNPs and additional covariates may predict cannabis use, measured on an ordinal scale as: “never tried,” “used moderately,” or “used frequently”. To conduct this analysis, we extended the ordinal Generalized Monotone Incremental Forward Stagewise (GMIFS) method for mixed models. This extension includes allowance for a unpenalized set of covariates to be coerced into the model as well as flexibility for user-specified correlation patterns between twins in a family. The proposed methods are applicable to high-dimensional (genomic or otherwise) data with ordinal response and specific, known covariance structure within clusters

State of Tennessee v. Sedrick Clayton

Student comments on the Tennessee Supreme Court decision “State of Tennessee v. Sedrick Clayton”. All defendants charged with crimes deserve a competent and rigorous defense because of the higher stakes in a criminal matter, the loss of liberty, and none more so than in a capital punishment case where the stakes for the defendant are at the highest—the loss of life. This case and the Court’s subsequent analysis illustrates the incredible importance of compliance with all procedural requirements when mounting a defense on behalf of a defendant, as the failure to comply with certain procedural rules ultimately resulted in the defendant waiving review of his Fourth Amendment violation claim on appeal. Despite this waiver, the Court of Criminal Appeals did conduct a review of his claim but because of that waiver, consideration of that claim was pursuant to the Court’s Plain Error Review, a much higher burden to meet. This case highlights the importance of ensuring they are complying with all procedural requirements at every stage of the litigation process and reaffirms that, though a person has enumerated constitutional rights, in order for your constitutional rights to be exercised, a defendant must do exactly that—make a clear showing of intent to exercise your rights. This right is not guaranteed unless it exercised properly

Patterns of Synorogenic Sedimentation Associated with the Unroofing of the Willard-Paris-Meade Thrust Sheets, Sevier Fold-Thrust Belt

The Willard-Paris-Meade thrust is the oldest and western-most sheet to develop in the Wyoming salient of the Sevier fold-thrust belt. The 10-15 km thick thrust sheet was emplaced ~60 km eastward and included Jurassic-Triassic strata, mixed siliciclastic-carbonate upper Paleozoic strata, carbonate-rich lower Paleozoic strata, and quartzite-rich basal Cambrian to Neoproterozoic strata. Each stratigraphic interval has a distinctive detrital zircon (DZ) age signature, which can be used in provenance analysis of foreland basin fill. The thrust system had a long deformation history recorded by westward thickening and coarsening synorogenic strata. DZ U-Pb geochronology of 27 synorogenic samples collected from two transects reveals an unroofing sequence with stratigraphically consistent changes in DZ patterns. DZ spectra for the Gannett Group in the lower part of the basin fill are consistent with erosion of Mesozoic to upper Paleozoic strata. Maximum depositional ages (MDA) from limited euhedral and likely volcanic grains for the foreland basin sequence show the following for the northern transect: basal Ephraim Formation, 150 ± 2.8 Ma (n=10); upper Ephraim, 115.2 ± 1.8 Ma (n=13); lower Bechler, 116.2 ± 2.3 Ma (n=9); upper Bechler 107.3 ± 3.3 Ma (n=4). These data clarify that there is not a significant unconformity at the base of the Bechler, and that the Bechler conglomerate facies at Red Mountain spans the depositional interval including the ~112 Ma Drainey Limestone, which is absent at Red Mountain but present elsewhere. The southern transect yields the following MDAs: Upper Gannett, 109 ± 6.1 Ma (n=5) and 108.3 ± 3.4 Ma (n=10); Cokeville, 101.6 ± 0.7 Ma (n=32); Lower Sage Junction 101.55 ± 0.5 Ma (n=67); Upper Sage Junction, 101.3 ± 0.6 Ma (n=29); Aspen, 98.8 ± 0.4 Ma (n=51); lower Frontier, 99.93 ± 0.6 Ma (n=21); upper Frontier, 95.68 ± 1.4 Ma (n=38). DZ spectra for the Bear River and Aspen formations in the middle part of the basin fill are consistent with erosion of mostly Paleozoic bedrock. DZ spectra in the Frontier Formation in the upper part of the basin fill are consistent with increased erosion of basal Cambrian and Neoproterozoic quartzites. The early history of deposition is elusive due to the potential bias from the early Cretaceous Sierran magmatic lull and a lack of datable materials related to corollary studies

Penalized Ordinal Regression Methods for Predicting Stage of Cancer in High-Dimensional Covariate Spaces

The pathological description of the stage of a tumor is an important clinical designation and is considered, like many other forms of biomedical data, an ordinal outcome. Currently, statistical methods for predicting an ordinal outcome using clinical, demographic, and high-dimensional correlated features are lacking. In this paper, we propose a method that fits an ordinal response model to predict an ordinal outcome for high-dimensional covariate spaces. Our method penalizes some covariates (high-throughput genomic features) without penalizing others (such as demographic and/or clinical covariates). We demonstrate the application of our method to predict the stage of breast cancer. In our model, breast cancer subtype is a nonpenalized predictor, and CpG site methylation values from the Illumina Human Methylation 450K assay are penalized predictors. The method has been made available in the ordinalgmifs package in the R programming environment

Persons with disabilities in Robeson County, North Carolina : an action-oriented community diagnosis : findings and next steps of action

The following document is a detailed report of an Action Oriented Community Diagnosis (AOCD) completed by a five-member team of graduate students at University of North Carolina at Chapel Hill, School of Public Health, Department of Health Behavior and Health Education. This AOCD was conducted in order to gain an understanding of the cultural, social, economic, and health experiences of persons with disabilities and their families in Robeson County, North Carolina. Through the AOCD process, the team and community participants identified resources, strengths, and challenges that exist in Robeson County for persons with disabilities and their families, and developed action steps to address several of the challenges. Over the course of seven months from October 2007 to April 2008, the team worked to learn more about the community. Through conducting secondary data, attending community events, and conducting 28 in-depth interviews with 20 service providers and eight community members and three focus groups with 13 community members, team members gained valuable insight into everyday life in this community. The team developed a coding system to analyze the data collected and to identify recurring themes related to living with disabilities in Robeson County. In April 2008, the team organized a community forum at the O.P. Owens Building in Lumberton, the county seat, to present findings from the AOCD process to over 43 community members and service providers. At the forum, participants had the opportunity to discuss major themes that emerged from the team‘s data analysis, and to work together in small groups to create specific action steps to address those themes. The themes and action steps discussed at the forum were: 1. Transportation: There is a lack of accessible, reliable, and affordable transportation options in Robeson County. This limits quality of life, access to services, and employment for people living with disabilities. Attend County Commissioner meetings. Attend Mayor‘s Committee for the Disabled meetings. Call SEATS to ask about safety procedures, weight limits, and wheelchair accessible vans. Research how other communities with similar demographics and geographies have addressed transportation for persons with disabilities. Look into recreating the voucher program. Create an education campaign for service providers, wheelchair vendors, persons with disabilities, and the general community about transportation issues faced by persons with disabilities. Talk to physicians and physical therapists about transportation issues faced by persons with disabilities, including how selection of wheelchair can affect opportunities for public transportation. 2. Services Communication and Information: Although many services exist for persons with disabilities in Robeson County, there is a lack of a centralized information system accessible to people with low literacy and without access to computer technology. There is also a lack of partnership between service providers. This causes confusion and limited knowledge about services for service providers, persons with disabilities and their families. Contacting the Healing Lodge in the county to facilitate a discussion with those members and connect them to disability resources. Service providers presenting at healthcare to educate the community about services available. Finding out more about the 211 telephone information service provided by United Way. Collaborate with other agencies on the Partnership for Community Health booklet by letting Partnership know about more providers. 3. Recreation: There is an interest among persons with disabilities to become physically active. There is a lack of recreational opportunities and facilities for persons with disabilities in Robeson County. This limits social and recreational interaction and creates barriers for physical fitness. Advertise and increase awareness of disabilities and recreational opportunities for persons with disabilities in the local newspapers. Form a support group for persons with disabilities to increase awareness of the need for recreation for persons with disabilities. Hold first meeting of support group where the ADA laws that ensure persons with disabilities access to accessible public recreational opportunities are explained. Organize monthly activities for persons with disabilities. 4. Awareness: There is limited awareness among community members and service providers about persons with disabilities, especially “invisible disabilities,” such as chronic illness and substance abuse. This contributes to feelings of isolation and disrespect that diminish the quality of life for persons with disabilities and caregivers. Train healthcare workers in disability awareness by having them use different assistance devices, such as wheelchairs, for a day. Be vocal as persons with disabilities and share experiences and perspectives with others. Advocate for disability awareness by integrating discussions of disability in other venues. Educate employers about ADA rights. 5. Paying for services: Although many people living with disabilities in Robeson County are supported by Medicaid, many others are uninsured and have difficulty paying for medical services. This causes people to delay seeking medical help and decreases the reach and effectiveness of existing resources. Action steps were not developed for this group as there were not enough attendees who participated in developing action steps around this theme. Following the forum, the team completed this final report with recommendations for the community based on their experiences throughout the process and the outcomes from the community forum. The final recommendations are summarized below: 1. Service providers for persons with disabilities in Robeson County should continue to update the resource list that the team has compiled and included in this document and should make it available in multiple formats designed for the those with vision loss, low literacy, and without access to computer technology. 2. Service providers for persons with disabilities in Robeson County should create a centralized referral system that could direct its users to different services, including medical and social services, as suggested by several service providers and community members. This could be started by further publicizing the existing 211 telephone directory. 3. Community members and service providers should advocate for the expansion of the county transit program (SEATS), including more accessible vans and drivers, affordable fares, and weekend routes. 4. Service providers should hold annual public events such as a community forum or health fair to increase awareness of disabilities and services and resources available to persons with disabilities in Robeson County. This can be hosted by a local health agency or an advocacy organization such as the Mayor‘s Committee for the Disabled. 5. Community members and service providers should advocate for the perspectives of persons with disabilities in public meetings about county development, including new and existing projects. Persons with disabilities and their supporters should be aware of local news, attend town, city or county meetings whenever possible, and share their views and ideas with the larger community. The Mayor‘s Committee for the Disabled should support persons with disabilities in these efforts by publicizing their meeting times and by helping persons with disabilities access schedules of other local government meetings and public hearings. The team hopes that this report, the action steps, community member and service provider connections, and the strong sense of initiative for change that emerged from this project and the community forum will continue to build on the strengths of this community. Ultimately, the team also hopes that the entire AOCD process and this final report contribute to future improvements not only for persons with disabilities, but for all residents of Robeson County.Master of Public Healt

Tailoring the nanoscale morphology of HKUST-1 thin films via codeposition and seeded growth

Integration of surface-anchored metal-organic frameworks (surMOFs) within hierarchical architectures is necessary for potential sensing, electronic, optical, or separation applications. It is important to understand the fundamentals of film formation for these surMOFs in order to develop strategies for their incorporation with nanoscale control over lateral and vertical dimensions. This research identified processing parameters to control the film morphology for surMOFs of HKUST-1 fabricated by codeposition and seeded deposition. Time and temperature were investigated to observe film formation, to control film thickness, and to tune morphology. Film thickness was investigated by ellipsometry, while film structure and film roughness were characterized by atomic force microscopy. Films formed via codeposition resulted in nanocrystallites anchored to the gold substrate. A dynamic process at the interface was observed with a low density of large particulates (above 100 nm) initially forming on the substrate; and over time these particulates were slowly replaced by the prevalence of smaller crystallites (ca. 10 nm) covering the substrate at a high density. Elevated temperature was found to expedite the growth process to obtain the full range of surface morphologies with reasonable processing times. Seed crystals formed by the codeposition method were stable and nucleated growth throughout a subsequent layer-by-layer deposition process. These seed crystals templated the final film structure and tailor the features in lateral and vertical directions. Using codeposition and seeded growth, different surface morphologies with controllable nanoscale dimensions can be designed and fabricated for integration of MOF systems directly into device architectures and sensor platforms

Tryptophane-205 of human topoisomerase I is essential for camptothecin inhibition of negative but not positive supercoil removal

Positive supercoils are introduced in cellular DNA in front of and negative supercoils behind tracking polymerases. Since DNA purified from cells is normally under-wound, most studies addressing the relaxation activity of topoisomerase I have utilized negatively supercoiled plasmids. The present report compares the relaxation activity of human topoisomerase I variants on plasmids containing equal numbers of superhelical twists with opposite handedness. We demonstrate that the wild-type enzyme and mutants lacking amino acids 1–206 or 191–206, or having tryptophane-205 replaced with a glycine relax positive supercoils faster than negative supercoils under both processive and distributive conditions. In contrast to wild-type topoisomerase I, which exhibited camptothecin sensitivity during relaxation of both negative and positive supercoils, the investigated N-terminally mutated variants were sensitive to camptothecin only during removal of positive supercoils. These data suggest different mechanisms of action during removal of supercoils of opposite handedness and are consistent with a recently published simulation study [Sari and Andricioaei (2005) Nucleic Acids Res., 33, 6621–6634] suggesting flexibility in distinct parts of the enzyme during clockwise or counterclockwise strand rotation

Correlations between life-detection techniques and implications for sampling site selection in planetary analog missions

We conducted an analog sampling expedition under simulated mission constraints to areas dominated by basaltic tephra of the Eldfell and Fimmvörðuháls lava fields (Iceland). Sites were selected to be “homogeneous” at a coarse remote sensing resolution (10–100 m) in apparent color, morphology, moisture, and grain size, with best-effort realism in numbers of locations and replicates. Three different biomarker assays (counting of nucleic-acid-stained cells via fluorescent microscopy, a luciferin/luciferase assay for adenosine triphosphate, and quantitative polymerase chain reaction (qPCR) to detect DNA associated with bacteria, archaea, and fungi) were characterized at four nested spatial scales (1 m, 10 m, 100 m, and >1 km) by using five common metrics for sample site representativeness (sample mean variance, group F tests, pairwise t tests, and the distribution-free rank sum H and u tests). Correlations between all assays were characterized with Spearman's rank test. The bioluminescence assay showed the most variance across the sites, followed by qPCR for bacterial and archaeal DNA; these results could not be considered representative at the finest resolution tested (1 m). Cell concentration and fungal DNA also had significant local variation, but they were homogeneous over scales of >1 km. These results show that the selection of life detection assays and the number, distribution, and location of sampling sites in a low biomass environment with limited a priori characterization can yield both contrasting and complementary results, and that their interdependence must be given due consideration to maximize science return in future biomarker sampling expeditions