Power Boosting in Genome-Wide Studies Via Methods for Multivariate Outcomes

Whole-genome studies are becoming a mainstay of biomedical research. Examples include expression array experiments, comparative genomic hybridization analyses and large case-control studies for detecting polymorphism/disease associations. The tactic of applying a regression model to every locus to obtain test statistics is useful in such studies. However, this approach ignores potential correlation structure in the data that could be used to gain power, particularly when a Bonferroni correction is applied to adjust for multiple testing. In this article, we propose using regression techniques for misspecified multivariate outcomes to increase statistical power over independence-based modeling at each locus. Even when the outcome is not ordinarily regarded as multivariate, it is mathematically valid to view the outcome as a set of (identical) repeated measurements, one associated with each genetic locus. Rather than joint modeling of all observations, we propose to apply joint modeling to subgroups of data. The primary example in this article focuses on the use of generalized estimating equations (GEE) software to apply the method. We describe conditions under which the proposed method provides more power than applying independence-based methods. In simulation studies of plausible and interesting scenarios, power gains are as large as 35% compared to modeling the outcomes univariately with a one genetic covariate. In contrast, modeling the outcome as univariate with multiple genetic covariates performs very poorly when data are correlated. The proposed method is easy to apply, allows adjustment for confounding and can be combined with other methods for increasing power in multiple testing situations

A new mixture model approach to analyzing allelic-loss data using Bayes factors

BACKGROUND: Allelic-loss studies record data on the loss of genetic material in tumor tissue relative to normal tissue at various loci along the genome. As the deletion of a tumor suppressor gene can lead to tumor development, one objective of these studies is to determine which, if any, chromosome arms harbor tumor suppressor genes. RESULTS: We propose a large class of mixture models for describing the data, and we suggest using Bayes factors to select a reasonable model from the class in order to classify the chromosome arms. Bayes factors are especially useful in the case of testing that the number of components in a mixture model is n(0 )versus n(1). In these cases, frequentist test statistics based on the likelihood ratio statistic have unknown distributions and are therefore not applicable. Our simulation study shows that Bayes factors favor the right model most of the time when tumor suppressor genes are present. When no tumor suppressor genes are present and background allelic-loss varies, the Bayes factors are often inconclusive, although this results in a markedly reduced false-positive rate compared to that of standard frequentist approaches. Application of our methods to three data sets of esophageal adenocarcinomas yields interesting differences from those results previously published. CONCLUSIONS: Our results indicate that Bayes factors are useful for analyzing allelic-loss data

A mixed-methods process evaluation of SafeTea: A multimedia campaign to prevent hot drink scalds in young children and promote burn first aid

Objectives: SafeTea is a multifaceted intervention delivered by community practitioners to prevent hot drink scalds to young children and improve parents’ knowledge of appropriate burn first aid. We adapted SafeTea for a national multimedia campaign, and present a mixed-methods process evaluation of the campaign. Methods: We used social media, a website hosting downloadable materials, and media publicity to disseminate key messages to parents/caregivers of young children and professionals working with these families across the UK. The SafeTea campaign was launched on National Burns Awareness Day (NBAD), October 2019, and ran for three months. Process evaluation measurements included social media metrics, Google Analytics, and quantitative and qualitative results from a survey of professionals who requested hard copies of the materials via the website. Results: Findings were summarised under four themes: “reach”, “engagement”, “acceptability”, and “impact/behaviour change”. The launch on NBAD generated widespread publicity. The campaign reached a greater number of the target audience than anticipated, with over 400,000 views of the SafeTea educational videos. Parents and professionals engaged with SafeTea and expressed positive opinions of the campaign and materials. SafeTea encouraged parents to consider how to change their behaviours to minimise the risks associated with hot drinks. Reach and engagement steadily declined after the first month due to reduced publicity and social media promotion. Conclusion: The SafeTea campaign was successful in terms of reach and engagement. The launch on NBAD was essential for generating media interest. Future campaigns could be shorter, with more funding for additional social media content and promotion

A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

<p>Abstract</p> <p>Background</p> <p>Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms.</p> <p>Results</p> <p>We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR.</p> <p>Conclusion</p> <p>Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 × 10^-6under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.</p

Disruption of Protein Kinase A in Mice Enhances Healthy Aging

Mutations that cause a reduction in protein kinase A (PKA) activity have been shown to extend lifespan in yeast. Loss of function of mammalian RIIβ, a regulatory subunit of PKA expressed in brain and adipose tissue, results in mice that are lean and insulin sensitive. It was therefore hypothesized that RIIB null (RIIβ−/−) mice would express anti-aging phenotypes. We conducted lifespan studies using 40 mutant and 40 wild type (WT) littermates of equal gender numbers and found that both the median and maximum lifespans were significantly increased in mutant males compared to WT littermates. The median lifespan was increased from 884 days to 1005 days (p = 0.006 as determined by the log rank test) and the 80% lifespan (defined here as 80% deaths) was increased from 941 days to 1073 days (p = 0.004 as determined by the Wang-Allison test). There was no difference in either median or 80% lifespan in female genotypes. WT mice of both genders became increasingly obese with age, while mutant mice maintained their lean phenotype into old age. Adiposity was found to correlate with lifespan for males only. 50% of male mice between 30 and 35 g, corresponding to about 5% body fat, for either genotype lived over 1000 days. No male mouse outside of this weight range achieved this lifespan. During their last month of life, WT mice began losing weight (a total of 8% and 15% of body weight was lost for males and females, respectively), but RIIβ−/− male mice maintained their lean body mass to end of life. This attenuation of decline was not seen in female mutant mice. Old male mutant mice were insulin sensitive throughout their life. Both genders showed modestly lower blood glucose levels in old mutants compared to WT. Male mutants were also resistant to age-induced fatty liver. Pathological assessment of tissues from end of life male mutant mice showed a decrease in tumor incidence, decreased severity of renal lesions, and a trend towards a decrease in age-related cardiac pathology. These findings help establish the highly conserved nature of PKA and suggest that disruption of PKA affects physiological mechanisms known to be associated with healthy aging

Genetic Modification of the Association between Peripubertal Dioxin Exposure and Pubertal Onset in a Cohort of Russian Boys

Background: Exposure to dioxins has been associated with delayed pubertal onset in both epidemiologic and animal studies. Whether genetic polymorphisms may modify this association is currently unknown. Identifying such genes could provide insight into mechanistic pathways. This is one of the first studies to assess genetic susceptibility to dioxins. Objectives: We evaluated whether common polymorphisms in genes affecting either molecular responses to dioxin exposure or pubertal onset influence the association between peripubertal serum dioxin concentration and male pubertal onset. Methods: In this prospective cohort of Russian adolescent boys (n = 392), we assessed gene–environment interactions for 337 tagging single-nucleotide polymorphisms (SNPs) from 46 candidate genes and two intergenic regions. Dioxins were measured in the boys’ serum at age 8–9 years. Pubertal onset was based on testicular volume and on genitalia staging. Statistical approaches for controlling for multiple testing were used, both with and without prescreening for marginal genetic associations. Results: After accounting for multiple testing, two tag SNPs in the glucocorticoid receptor (GR/NR3C1) gene and one in the estrogen receptor-α (ESR1) gene were significant (q < 0.2) modifiers of the association between peripubertal serum dioxin concentration and male pubertal onset defined by genitalia staging, although not by testicular volume. The results were sensitive to whether multiple comparison adjustment was applied to all gene–environment tests or only to those with marginal genetic associations. Conclusions: Common genetic polymorphisms in the glucocorticoid receptor and estrogen receptor-α genes may modify the association between peripubertal serum dioxin concentration and pubertal onset. Further studies are warranted to confirm these findings

Age of Pseudomonas aeruginosa acquisition and subsequent severity of cystic fibrosis lung disease

Rationale: Pseudomonas aeruginosa (Pa) is associated with poor pulmonary outcomes in cystic fibrosis (CF), but the association between age of Pa infection and severity of subsequent lung disease has not been thoroughly investigated. Objective: Our goal was to determine the association between age of Pa acquisition and subsequent severity of CF lung disease. Methods: Case–control study using CF Foundation Registry data of 629 ΔF508 homozygotes with severe and mild lung disease (FEV1 in the lowest and highest quartile of birth cohort, respectively). Multivariate logistic regression was performed to determine the association between age of Pa acquisition and lung disease severity. Results: Earlier age of Pa infection was strongly associated with increased odds of severe lung disease. For first and persistent Pa, adjusted odds ratios for severe lung disease were 6.5 (95% CI 3.1, 13.7; P < 0.0001) and 11.2 (5.4, 23.1; P < 0.0001), respectively, for subjects with infection before age 5 versus at ≥10 years; the association was stronger in females than males. Conclusions: Earlier Pa infection, particularly before 5 years of age, is strongly associated with severe CF lung disease later in life. This study is not designed to determine causality; Pa infection may be causing lung injury, or may be a marker of ongoing inflammation and lung damage in young children with CF

Temporal trends in serum concentrations of polychlorinated dioxins, furans, and PCBs among adult women living in Chapaevsk, Russia: a longitudinal study from 2000 to 2009

<p>Abstract</p> <p>Background</p> <p>The present study assessed the temporal trend in serum concentrations of polychlorinated dibenzo-<it>p</it>-dioxins, dibenzofurans, and biphenyls (PCBs) among residents of a Russian town where levels of these chemicals are elevated due to prior industrial activity.</p> <p>Methods</p> <p>Two serum samples were collected from eight adult women (in 2000 and 2009), and analyzed with gas chromatography-high-resolution mass spectrometry.</p> <p>Results</p> <p>The average total toxic equivalency (TEQ) decreased by 30% (from 36 to 25 pg/g lipid), and the average sum of PCB congeners decreased by 19% (from 291 to 211 ng/g lipid). Total TEQs decreased for seven of the eight women, and the sum of PCBs decreased for six of eight women. During this nine year period, larger decreases in serum TEQs and PCBs were found in women with greater increases in body mass index.</p> <p>Conclusions</p> <p>This study provides suggestive evidence that average serum concentrations of dioxins, furans, and PCBs are decreasing over time among residents of this town.</p