Robust Distributed Lag Models with Multiple Pollutants using Data Adaptive Shrinkage

There is growing interest in investigating the short-term delayed lag effects of environmental pollutants (e.g. air particulate matter and ozone) on a health outcome of interest measured at a certain time (e.g. daily mortality counts). Previous studies have shown that not only the current level of the exposure but exposure levels up to past few days may be associated with health event/outcome measured on current day. Distributed lag model (DLM) has been used in environmental epidemiology to characterize the lag structure of exposure effects. These models assume that the coefficients corresponding to exposures at different lags follow a given function of the lags. Under mis-specification of this function, DLM can lead to seriously biased estimates. In this dissertation, we first explore different methods to make the traditional DLM more robust. We then extend the single pollutant DLM to multi-pollutant scenarios. We illustrate the proposed methods using air pollution data from the National Morbidity, Mortality and Air Pollution Study (NMMAPS) and a dataset from Brigham and Women's Hospital (BWH) prospective birth cohort study. In the first project, we propose three classes of shrinkage methods to combine an unconstrained DLM estimator and a constrained DLM estimator and achieve a balance between robustness and efficiency. The three classes of methods can be broadly described as (1) empirical Bayes-type shrinkage, (2) hierarchical Bayes, and (3) generalized ridge regression. A two-step double shrinkage approach that enforces the effect estimates approach zero at larger lags is also considered. A simulation study shows that all four approaches are effective in trading off between bias and variance to attain lower mean squared error with the two-step approaches having edge over others. In the second project, we extend DLM to two-pollutant scenarios and focus on characterizing pollutant-by-pollutant interaction. We first consider to model the interaction surface by assuming the underlying basis functions are tensor products of the basis functions that generate the main-effect distributed lag functions. We also extend Tukey's one-degree-of-freedom interaction model to two-dimensional DLM context as a parsimonious way to model the interaction surface between two pollutants. Data adaptive approaches to allow departure from the specified Tukey's structure are also considered. A simulation study shows that shrinkage approach Bayesian constrained DLM has the best average performance in terms of relative efficiency. In the third project, we extend DLM to a truly multi-dimensional space and focus on identifying important pollutants and pairwise interactions associated with a health outcome. Penalization-based approaches that induce sparsity in solution are considered. We propose a Hierarchical integrative Group LASSO (HiGLASSO) approach to perform variable selection at a group level while maintaining strong heredity constraints. Empirically, HiGLASSO identifies the correct set of important variables more frequently than other approaches. Theoretically, we show that HiGLASSO enjoys Oracle properties including selection and estimation consistency.PHDBiostatisticsUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/138649/1/yinhsiuc_1.pd

Joint Rare Variant Association Test of the Average and Individual Effects for Sequencing Studies

For many complex traits, single nucleotide polymorphisms (SNPs) identified from genome-wide association studies (GWAS) only explain a small percentage of heritability. Next generation sequencing technology makes it possible to explore unexplained heritability by identifying rare variants (RVs). Existing tests designed for RVs look for optimal strategies to combine information across multiple variants. Many of the tests have good power when the true underlying associations are either in the same direction or in opposite directions. We propose three tests for examining the association between a phenotype and RVs, where two of them jointly consider the common association across RVs and the individual deviations from the common effect. On one hand, similar to some of the best existing methods, the individual deviations are modeled as random effects to borrow information across multiple RVs. On the other hand, unlike the existing methods which pool individual effects towards zero, we pool them towards a possibly non-zero common effect by adding a pooled variant into the model. The common effect and the individual effects are jointly tested. We show through extensive simulations that at least one of the three tests proposed here is the most powerful or very close to being the most powerful in various settings of true models. This is appealing in practice because the direction and size of the true effects of the associated RVs are unknown. Researchers can apply the developed tests to improve power under a wide range of true models

Distributed lag interaction models with two pollutants

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146866/1/rssc12297.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146866/2/rssc12297_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146866/3/rssc12297-sup-0001-Appendix.pd

Selection of nonlinear interactions by a forward stepwise algorithm: Application to identifying environmental chemical mixtures affecting health outcomes

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149279/1/sim8059_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149279/2/SIM_8059-Supp-0001-InteractionSelection_Supp.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149279/3/sim8059.pd

Precocious puberty in patients with Pompe disease

IntroductionThe life expectancy of Pompe disease patients has increased due to improved neonatal screening and enzyme replacement therapy. Nevertheless, the potential effect of frequent medical device exposure on pubertal development in these patients is not well understood, so further investigation is warranted.MethodsIn this cross-sectional study, we assessed the growth and puberty of nine Pompe disease patients. In addition, to determine the effects of frequent plastic medical device exposure in these patients, we measured urinary phthalate metabolites before and one day after enzyme replacement therapy.ResultsFive out of nine patients (55%) with Pompe disease on enzyme replacement therapy had precocious puberty. Patients with precocious puberty had significantly shorter predicted adult heights compared to those with normal puberty (p = 0.014). The levels of mono-2-ethylhexyl phthalate (MEHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) increased after enzyme replacement therapy, but the average levels of phthalate metabolites did not significantly differ between patients with normal and precocious puberty.ConclusionPompe disease patients on enzyme replacement therapy tend to have precocious puberty, which may reduce their adult height. There are no significant differences in urinary phthalate metabolites between normal and precocious puberty patients. Regular follow-up of growth and puberty in Pompe disease patients is important to improve their health outcomes

The Untranslated Regions of Classic Swine Fever Virus RNA Trigger Apoptosis

Classical swine fever virus (CSFV) causes a broad range of disease in pigs, from acute symptoms including high fever and hemorrhages, to chronic disease or unapparent infection, depending on the virus strain. CSFV belongs to the genus Pestivirus of the family Flaviviridae. It carries a single-stranded positive-sense RNA genome. An internal ribosomal entry site (IRES) in the 5' untranslated region (UTR) drives the translation of a single open reading frame encoding a 3898 amino acid long polypeptide chain. The open reading frame is followed by a 3' UTR comprising four highly structured stem-loops. In the present study, a synthetic RNA composed of the 5' and 3' UTRs of the CSFV genome devoid of any viral coding sequence and separated by a luciferase gene cassette (designated 5'UTR-Luc-3'UTR) triggered apoptotic cell death as early as 4 h post-transfection. The apoptosis was measured by DNA laddering analysis, TUNEL assay, annexin-V binding determined by flow cytometry, and by analysis of caspase activation. Contrasting with this, only trace DNA laddering was observed in cells transfected with the individual 5' or 3' UTR RNA; even when the 5' UTR and 3' UTR were co-transfected as separate RNA molecules, DNA laddering did not reach the level induced by the chimeric 5'UTR-Luc-3'UTR RNA. Interestingly, RNA composed of the 5'UTR and of stem-loop I of the 3'UTR triggered much stronger apoptosis than the 5' or 3'UTR alone. These results indicate that the 5' and 3' UTRs act together in cis induce apoptosis. We furthered obtained evidence that the UTR-mediated apoptosis required double-stranded RNA and involved translation shutoff possibly through activation of PKR

Relationships between serum HER2 ECD, TIMP-1 and clinical outcomes in Taiwanese breast cancer

<p>Abstract</p> <p>Background</p> <p>Serum levels of the extracellular domain of HER2/neu (HER2 ECD) have been demonstrated to be associated with clinical outcomes. A disintegrin and metalloproteinase-10, a sheddase of HER2/neu, can drive cancer progression and its activity is inhibited by tissue inhibitor of metalloproteinase-1 (TIMP-1). However, elevated TIMP-1 expression has been associated with a poor prognosis of breast cancer. Therefore, this study was performed to explore the relationships between serum HER2 ECD, TIMP-1 and clinical outcomes.</p> <p>Methods</p> <p>One hundred and eighty-five female breast cancer patients, who received curative mastectomy without neo-adjuvant chemotherapy at Chang-Gung Memorial Hospital, were recruited with informed consent for this study. Pre-operative serum levels of HER2 ECD and TIMP-1 were measured using an enzyme-linked immunosorbent assay.</p> <p>Results</p> <p>Twenty-three cases (12.4%) were classified HER2 ECD positive. HER2 ECD positivity was significantly associated with age, lymph node involvement, histological grade, estrogen receptor status, progesterone receptor status, tissue HER2/neu overexpression, and disease-free survival (DFS). In an age, stage, ER and HER2/neu status matched subgroup (N = 41), the serum level of TIMP-1 was significantly associated with HER2 ECD positivity and DFS.</p> <p>Conclusions</p> <p>A high serum TIMP-1 was significantly associated with HER2 ECD positivity and a poorer DFS among Taiwanese primary breast cancer patients with HER2 overexpression.</p

COMPARISON OF TORSO TWIST BETWEEN SLAP HIT AND ORDINARY HIT IN SOFTBALL BATTING

Softball batters take advantage of slap hit, by positioning the batters much closer to the first base. The purpose of this study was to compare the difference of torso twist between a slap hit and an ordinary hit in softball batting. Ten female college softball batters performed slap hits and ordinary hits. Reflective markers were placed on specific landmarks for each subject and VICON motion analysis system was used to record the hits. Slap hits showed less backward rotation during the torso wind-up phase while ordinary hit showed more forward rotation during the torso follow-through phase. No difference on trunk rotation was found at impact. The findings of this study suggested that the restricted backward torso twist during the wind-up phase and the limited forward torso twist during the follow-through phase should be taken into consideration in slap hits