Many genome-wide association studies (GWAS) have signals with unknown etiology. This paper addresses the question—is such an association signal caused by rare or common variants that lead to increased disease risk? For a genomic region implicated by a GWAS, we use single nucleotide polymorphism (SNP) data in a case-control setting to predict how many common or rare variants there are, using a Bayesian analysis. Our objective is to compute posterior probabilities for configurations of rare and/or common variants. We use an extension of coalescent trees—the ancestral recombination graphs—to model the genealogical history of the samples based on marker data. As we expect SNPs to be in linkage disequilibrium with common disease variants, we can expect the trees to reflect the type of variants. To demonstrate the application, we apply our method to candidate gene sequencing data from a German case-control study on nonsyndromic cleft lip with or without cleft palate. Genet. Epidemiol. 36:419-429, 2012. © 2012 Wiley Periodicals, Inc.
Monday, April 30, 2012
Reprioritizing Genetic Associations in Hit Regions Using LASSO-Based Resample Model Averaging
Significance testing one SNP at a time has proven useful for identifying genomic regions that harbor variants affecting human disease. But after an initial genome scan has identified a “hit region” of association, single-locus approaches can falter. Local linkage disequilibrium (LD) can make both the number of underlying true signals and their identities ambiguous. Simultaneous modeling of multiple loci should help. However, it is typically applied ad hoc: conditioning on the top SNPs, with limited exploration of the model space and no assessment of how sensitive model choice was to sampling variability. Formal alternatives exist but are seldom used. Bayesian variable selection is coherent but requires specifying a full joint model, including priors on parameters and the model space. Penalized regression methods (e.g., LASSO) appear promising but require calibration, and, once calibrated, lead to a choice of SNPs that can be misleadingly decisive. We present a general method for characterizing uncertainty in model choice that is tailored to reprioritizing SNPs within a hit region under strong LD. Our method, LASSO local automatic regularization resample model averaging (LLARRMA), combines LASSO shrinkage with resample model averaging and multiple imputation, estimating for each SNP the probability that it would be included in a multi-SNP model in alternative realizations of the data. We apply LLARRMA to simulations based on case-control genome-wide association studies data, and find that when there are several causal loci and strong LD, LLARRMA identifies a set of candidates that is enriched for true signals relative to single locus analysis and to the recently proposed method of Stability Selection. Genet. Epidemiol. 36:451-462, 2012. © 2012 Wiley Periodicals, Inc.
Enthusiastic Improvement: Mary Astell and Damaris Masham on Sociability
Many commentators have contrasted the way that sociability is theorized in the writings of Mary Astell and Damaris Masham, emphasizing the extent to which Masham is more interested in embodied, worldly existence. I argue, by contrast, that Astell's own interest in imagining a constitutively relational individual emerges once we pay attention to her use of religious texts and tropes. To explore the relevance of Astell's Christianity, I emphasize both how Astell's Christianity shapes her view of the individual's relation to society and how Masham's contrasting views can be analyzed through the lens of her charge that Astell is an “enthusiast.” In late seventeenth-century England, “enthusiasm” was a term of abuse that, commentators have recently argued, could function polemically to dismiss those deemed either excessively social or antisocial. By accusing Astell of enthusiasm, I claim, Masham seeks to marginalize the relational self that Astell imagines and to promote a more instrumental view of social ties. I suggest some aspects of Astell's thought that may have struck contemporaries as “enthusiastic” and contrast her vision of the self with Masham's more hedonistic subject. I conclude that, although each woman differently configures the relation between self and society, they share a desire to imagine autonomy within a relational framework.
Chronic rhinosinusitis symptoms and computed tomography staging: improved correlation by incorporating radiographic density
Abstract
Background:
Traditional methods for staging of chronic rhinosinusitis (CRS) by computed tomography (CT) have not proven to be predictive of subjective reports of patients' symptoms. An objective measure of CRS severity that correlates well with patients' symptoms, particularly if available from CT data, would be a valuable tool in assessment of disease status and outcomes after surgery.
Methods:
Retrospective chart review of CRS patients with symptom data from the Rhinosinusitis Symptom Inventory (RSI) and objective data from a sinus CT scan. CRS disease severity on CT imaging was measured according to the traditional Lund-Mackay scoring, as well as by raw measures of the densities of sinus opacities (in Hounsfield units [HU]) and density-weighted Lund-Mackay scoring. These data were related to symptom severity scores using a multivariate regression model.
Results:
There was no significant correlation between either raw density values of sinus opacities or weighted Lund-Mackay scores with facial or total symptom scores. Oropharyngeal symptoms scores were negatively correlated with the sum of “average HU” values (p = 0.036, β = −1.120) but were positively correlated with the sum of “maximum HU” values (p = 0.047, β = 1.221). There was a significant negative correlation between the systemic symptoms score and mean of “average HU” values (p = 0.010, β = −0.272). Finally, there was a positive correlation between “maximum HU” value-weighted Lund-Mackay score with nasal symptom scores (p = 0.016, β = 0.241), systemic symptom scores (p = 0.008, β = 0.605), and total symptom scores (p = 0.078, β = 0.179).
Conclusion:
Incorporation of radiographic characteristics of sinus opacification with Lund-Mackay scores offers greater predictive power of patients' subjective symptom severity. © 2012 ARS-AAOA, LLC.
Toward a Postcolonial, Posthumanist Feminist Theory: Centralizing Race and Culture in Feminist Work on Nonhuman Animals
Posthumanist feminist theory has been instrumental in demonstrating the salience of gender and sexism in structuring human–animal relationships and in revealing the connections between the oppression of women and of nonhuman animals. Despite the richness of feminist posthumanist theorizations it has been suggested that their influence in contemporary animal ethics has been muted. This marginalization of feminist work—here, in its posthumanist version—is a systemic issue within theory and needs to be remedied. At the same time, the limits of posthumanist feminist theory must also be addressed. Although posthumanist feminist theory has generated a sophisticated body of work analyzing how gendered and sexist discourses and practices subordinate women and animals alike, its imprint in producing intersectional analyses of animal issues is considerably weaker. This leaves theorists vulnerable to charges of essentialism, ethnocentrism, and elitism despite best intentions to avoid such effects and despite commitments to uproot all forms of oppression. Gender-focused accounts also preclude understanding of the importance of race and culture in structuring species-based oppression. To counter these undesirable pragmatic and conceptual developments, posthumanist feminist theory needs to engender feminist accounts that centralize the structural axes of race and culture.
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