Data Analysis And Study Design In The Presence Of Error-prone Diagnostic Tests

Interval censored time to event outcomes arise when a silent event of interest is known to have occurred within a specific time period, determined by the times of the last negative and first positive diagnostic tests. The four chapters comprising this thesis are tied together by a common theme in that the outcome of interest is an interval censored time to event random variable. In Chapter 1, we describe a stratified Weibull model appropriate for interval cen- sored outcomes and implement a new R package straweib. We compare the proposed approach with the log-linear form of the Weibull regression model that is currently im- plemented in the existing R package survival, and illustrate its use by analyzing data from a longitudinal oral health study on the timing of the emergence of permanent teeth in 4430 children. In Chapter 2, we present methods to estimate the association of one or more covariates with an error-prone, self reported time to event outcome. We present simulation studies to assess the effect of error in self reported outcomes with regard to bias in the estimation of the regression parameter of interest. We apply the proposed methods to the data from Women’s Health Initiative (WHI) to evaluate the effect of statin use with respect to incident diabetes risk. In Chapter 3, we develop tools to calculate power and sample size for studies in which data from sequentially administered, error-prone, laboratory-based diagnostic tests or self-reported questionnaires are collected to determine the occurrence of a silent event. We evaluate the effects of the characteristics of the imperfect diagnos- tic test on resulting power and sample size calculations. We compare the relative efficiency of various study designs in the context of error-prone outcomes. In Chapter 4, we propose a lasso and a Bayesian variable selection approach in the context of error-prone self reported outcomes to address the problem of vari- able selection in high dimensional data settings. We perform simulation studies to compare prediction performance of proposed methods and naive methods that ignore measurement error. We apply our proposed methods to the genome-wide association study data from the WHI to select biomarkers associated with diabetes

Bayesian variable selection for high dimensional predictors and self-reported outcomes

BACKGROUND: The onset of silent diseases such as type 2 diabetes is often registered through self-report in large prospective cohorts. Self-reported outcomes are cost-effective; however, they are subject to error. Diagnosis of silent events may also occur through the use of imperfect laboratory-based diagnostic tests. In this paper, we describe an approach for variable selection in high dimensional datasets for settings in which the outcome is observed with error. METHODS: We adapt the spike and slab Bayesian Variable Selection approach in the context of error-prone, self-reported outcomes. The performance of the proposed approach is studied through simulation studies. An illustrative application is included using data from the Women\u27s Health Initiative SNP Health Association Resource, which includes extensive genotypic ( \u3e 900,000 SNPs) and phenotypic data on 9,873 African American and Hispanic American women. RESULTS: Simulation studies show improved sensitivity of our proposed method when compared to a naive approach that ignores error in the self-reported outcomes. Application of the proposed method resulted in discovery of several single nucleotide polymorphisms (SNPs) that are associated with risk of type 2 diabetes in a dataset of 9,873 African American and Hispanic participants in the Women\u27s Health Initiative. There was little overlap among the top ranking SNPs associated with type 2 diabetes risk between the racial groups, adding support to previous observations in the literature of disease associated genetic loci that are often not generalizable across race/ethnicity populations. The adapted Bayesian variable selection algorithm is implemented in R. The source code for the simulations are available in the Supplement. CONCLUSIONS: Variable selection accuracy is reduced when the outcome is ascertained by error-prone self-reports. For this setting, our proposed algorithm has improved variable selection performance when compared to approaches that neglect to account for the error-prone nature of self-reports

Merger-induced star formation in low-metallicity dwarf galaxy NGC 4809/4810

The physical mechanisms driving starbursts in dwarf galaxies are unclear, and the effects of mergers on star formation in these galaxies are still uncertain. We explore how the merger process affects star formation in metal-poor dwarf galaxies by analyzing high-spatial-resolution ($\sim$ 70 pc) integral field spectrograph observations of ionized gas. We use archival data from the Very Large Telescope/Multi Unit Spectroscopic Explorer to map the spatial distribution of strong emission lines (e.g., $\rm H\beta$, $\rm H\alpha$, $\rm [OIII]\lambda5007$, $\rm [NII]\lambda6583$, etc) in the nearby merging star-forming dwarf galaxy system NGC 4809/4810. We identify approximately 112 star-forming knots scattered among the two galaxies, where the gas-phase metallicity distribution is inhomogeneous and mixing with metal-poor and metal-rich ionized gas. Star-forming knots at the interacting region show lower metallicity, the highest star formation rates (SFRs) and SFR to resolved main-sequence-relation (rMSR) ratios. Ionized gas exhibits an obvious northeast-southwest velocity gradient in NGC 4809, while seemingly mixed in NGC 4810. High virial parameters and the stellar mass-size relation of HII regions indicate that these regions are dominated by direct radiation pressure from massive stars/clusters and persistently expanding. We find two different stellar mass surface density-stellar age relations in NGC 4809 and NGC 4810, and the stellar ages of NGC 4810 are systematically younger than in NGC 4809. Our study suggests that the merging stage of two dwarf galaxies can induce starburst activities at the interaction areas, despite the metal-deficient environment. Considering the high specific SFRs and different stellar ages, we propose that the interaction initially triggered star formation in NGC 4809 and then drove star formation in NGC 4810.Comment: 13 pages, 12 figures; accepted for publication in A&

Marginal structural models for the estimation of the risk of Diabetes Mellitus in the presence of elevated depressive symptoms and antidepressant medication use in the Women\u27s Health Initiative observational and clinical trial cohorts

BACKGROUND: We evaluate the combined effect of the presence of elevated depressive symptoms and antidepressant medication use with respect to risk of type 2 diabetes among approximately 120,000 women enrolled in the Women\u27s Health Initiative (WHI), and compare several different statistical models appropriate for causal inference in non-randomized settings. METHODS: Data were analyzed for 52,326 women in the Women\u27s Health Initiative Clinical Trials (CT) Cohort and 68,169 women in the Observational Study (OS) Cohort after exclusions. We included follow-up to 2005, resulting in a median duration of 7.6 years of follow up after enrollment. Results from three multivariable Cox models were compared to those from marginal structural models that included time varying measures of antidepressant medication use, presence of elevated depressive symptoms and BMI, while adjusting for potential confounders including age, ethnicity, education, minutes of recreational physical activity per week, total energy intake, hormone therapy use, family history of diabetes and smoking status. RESULTS: Our results are consistent with previous studies examining the relationship of antidepressant medication use and risk of type 2 diabetes. All models showed a significant increase in diabetes risk for those taking antidepressants. The Cox Proportional Hazards models using baseline covariates showed the lowest increase in risk , with hazard ratios of 1.19 (95 % CI 1.06 - 1.35) and 1.14 (95 % CI 1.01 - 1.30) in the OS and CT, respectively. Hazard ratios from marginal structural models comparing antidepressant users to non-users were 1.35 (95 % CI 1.21 - 1.51) and 1.27 (95 % CI 1.13 - 1.43) in the WHI OS and CT, respectively - however, differences among estimates from traditional Cox models and marginal structural models were not statistically significant in both cohorts. One explanation suggests that time-dependent confounding was not a substantial factor in these data, however other explanations exist. Unadjusted Cox Proportional Hazards models showed that women with elevated depressive symptoms had a significant increase in diabetes risk that remained after adjustment for confounders. However, this association missed the threshold for statistical significance in propensity score adjusted and marginal structural models. CONCLUSIONS: Results from the multiple approaches provide further evidence of an increase in risk of type 2 diabetes for those on antidepressants

Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants

Background: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown. Methods: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis. Results: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3\u27 flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P\u3c5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci. Conclusions: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. (ClinicalTrials.gov number, NCT00242125.

Perioperative dynamic alterations in peripheral regulatory T and B cells in patients with hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Intratumoral and circulating regulatory T cells (Tregs) have been shown to be critical in the pathogenesis of hepatocellular carcinoma (HCC). However there is limited knowledge on the alterations of regulatory B cells (Bregs). We here investigated perioperative dynamic alterations of peripheral circulating Tregs and Bregs in HCC patients to reveal the relationship between regulatory lymphocytes and its clinical implications.</p> <p>Methods</p> <p>36 patients with HCC, 6 with chronic hepatitis B infection and 10 healthy donors were enrolled for this study. Frequencies of peripheral Tregs and Bregs were measured by flow cytometry with antibodies against CD4, CD25, CD127, CD19 and IL-10 before, and after radical surgery. Then, clinical informatics of HCC patients was achieved through Digital Evaluation Score System (DESS) for the assessment of disease severity. Finally, we analysed correlations between digitalized clinical features and kinetics of circulating regulatory lymphocytes.</p> <p>Results</p> <p>Level of circulating CD4⁺CD25⁺CD127^-Tregs in HCC patients was significantly lower than that in healthy donors and patients with chronic hepatitis B infection before surgery, but was increased after surgery. Preoperative level of CD19⁺IL-10⁺Bregs in HCC patients was also significantly lower than the other groups. However it dramatically was elevated right after surgery and remained elevated compared to controls (about 7 days after surgery, <it>P </it>= 0.04). Frequency of circulating Tregs was correlated with circulating leukocytes, ferritin, and clinical features suggesting tumor aggressiveness including portal vein thrombosis, hepatic vein involvement and advanced clinical stages. Frequency of circulating Bregs was associated with Hepatitis B e Antigen (HBeAg) and Hepatitis B virus (HBV) DNA copy number. In addition, DESS was significantly and positively correlated with other staging systems.</p> <p>Conclusion</p> <p>Frequencies of peripheral Tregs and Bregs in HCC patients increased after surgery. These results suggest that a postoperative combination of therapies against Tregs and Bregs may be beneficial for better outcome of HCC patients after resection.</p

Evaluation of SLOG/TCI-III pediatric system on target control infusion of propofol

<p>Abstract</p> <p>Background</p> <p>The target-controlled infusion-III (SLOG/TCI-III) system was derived from a model set up by the local pediatric population for target control infusion of propofol.</p> <p>Methods</p> <p>The current study aimed at evaluating the difference between target concentrations of propofol and performance, which was measured using the SLOG/TCI-III system in children. Thirty children fulfilling the I-II criteria according to American Society of Anesthesiology were enrolled in the study. The target plasma concentration of propofol was fed into the SLOG/TCI-III system and compared with the measured concentrations of propofol. Blood samples were collected and analyzed by high performance liquid chromatography with fluorescence detector. The performance error (PE) was determined for each measured blood propofol concentration. The performances of the TCI-III system were determined by the median performance error (MDPE), the median absolute performance error (MDAPE), and Wobble (the median absolute deviation of each PE from the MDPE), respectively.</p> <p>Results</p> <p>Concentration against target concentration showed good linear correlation: concentration = 1.3428 target concentration - 0.2633 (r = 0.8667). The MDPE and MDAPE of the pediatric system were 10 and 22%, respectively, and the median value for Wobble was 24%. MDPE and MDAPE were less than 15 and 30%, respectively.</p> <p>Conclusions</p> <p>The performance of TCI-III system seems to be in the accepted limits for clinical practice in children.</p

Gene Expression Analysis in Rats Treated with Experimental Acetyl-Coenzyme A Carboxylase Inhibitors Suggests Interactions with the Peroxisome Proliferator-Activated Receptor ␣ Pathway

ABSTRACT Acetyl CoA carboxylase (ACC) 2, which catalyzes the carboxylation of acetyl-CoA to form malonyl-CoA, has been identified as a potential target for type 2 diabetes and obesity. Small-molecule inhibitors of ACC2 would be expected to reduce de novo lipid synthesis and increase lipid oxidation. Treatment of ob/ob mice with compound A-908292 (S) ({(S)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methylprop-2-ynyl}-carbamic acid methyl ester), a small-molecule inhibitor with an IC 50 of 23 nM against ACC2, resulted in a reduction of serum glucose and triglyceride levels. However, compound A-875400 (R) ({(R)-3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynyl}-carbamic acid methyl ester), an inactive enantiomer of A-908292 (S) with approximately 50-fold less activity against ACC2, also caused a similar reduction in glucose and triglycerides, suggesting that the glucose-lowering effects in ob/ob mice may be mediated by other metabolic pathways independent of ACC2 inhibition. To characterize the pharmacological activity of these experimental compounds at a transcriptional level, rats were orally dosed for 3 days with either A-908292 (S) or A-875400 (R), and gene expression analysis was performed. Gene expression analysis of livers showed that treatment with A-908292 (S) or A-875400 (R) resulted in gene expression profiles highly similar to known peroxisome proliferator-activated receptor (PPAR)-␣ activators. The results suggest that, in vivo, both A-908292 (S) and A-875400 (R) stimulated the PPAR-␣-dependent signaling pathway. These results were further supported by both an in vitro genomic evaluation using rat hepatocytes and immunohistochemical evaluation using 70-kDa peroxisomal membrane protein. Overall, the gene expression analysis suggests a plausible mechanism for the similar pharmacological findings with active and inactive enantiomers of an ACC2 inhibitor