Gene, region and pathway level analyses in whole-genome studies.

In the setting of genome-wide association studies, we propose a method for assigning a measure of significance to pre-defined sets of markers in the genome. The sets can be genes, conserved regions, or groups of genes such as pathways. Using the proposed methods and algorithms, evidence for association between a particular functional unit and a disease status can be obtained not just by the presence of a strong signal from a SNP within it, but also by the combination of several simultaneous weaker signals that are not strongly correlated. This approach has several advantages. First, moderately strong signals from different SNPs are combined to obtain a much stronger signal for the set, therefore increasing power. Second, in combination with methods that provide information on untyped markers, it leads to results that can be readily combined across studies and platforms that might use different SNPs. Third, the results are easy to interpret, since they refer to functional sets of markers that are likely to behave as a unit in their phenotypic effect. Finally, the availability of gene-level P-values for association is the first step in developing methods that integrate information from pathways and networks with genome-wide association data, and these can lead to a better understanding of the complex traits genetic architecture. The power of the approach is investigated in simulated and real datasets. Novel Crohn's disease associations are found using the WTCCC data.

A signature of evolutionary constraint on a subset of ectopically expressed olfactory receptor genes.

Olfactory receptor (OR) genes constitute the basis for the sense of smell. It has long been observed that a subset of mammalian OR genes are expressed in nonolfactory tissues, in addition to their expression in the olfactory epithelium. However, it is unknown whether OR genes have alternative functions in the nonolfactory tissues. Using a dedicated microarray, we surveyed OR gene expression in olfactory epithelium as well as a number of nonolfactory tissues, in human and chimpanzee. Our observations suggest that ectopically expressed OR orthologous genes are expressed in the same nonolfactory tissues in human and chimpanzee more often than expected by chance alone. Moreover, we found that the subset of orthologous OR genes with conserved ectopic expression evolve under stronger evolutionary constraint than OR genes expressed exclusively in the olfactory epithelium. Thus, although we cannot provide direct functional data, our observations are consistent with the notion that a subset of ectopically expressed OR genes have additional functions in nonolfactory tissues.

Concordancia citocolposcópica con la prueba histopatológica en la identificación de neoplasias intraepiteliales cervicales / Cytocolposcopic concordance with histopathologic testing in the identification of cervical intraepithelial neoplasia

Resumen OBJETIVO: Evaluar la concordancia diagnóstica entre la citología y la colposcopia respecto del diagnóstico histopatológico de cáncer cervicouterino en mujeres del estado de San Luis Potosí que acudieron a un hospital de segundo nivel de atención. MATERIALES Y MÉTODOS: Estudio correlacional efectuado en un hospital de segundo nivel de atención del Municipio de San Luis Potosí, entre 2015 y 2017. Criterios de inclusión: reunir tres reportes de las pruebas de Papanicolaou, colposcopia e histopatología basados en la clasificación de Richart, ser usuarias de la clínica de colposcopia del hospital y haber firmado el consentimiento informado. Para evaluar la concordancia diagnóstica, tomando como referencia el resultado histopatológico, se realizó la prueba de Kappa. RESULTADOS: Se estudiaron 379 pacientes con media de edad de 34.61 años. La sensibilidad, especificidad, valor predictivo positivo y negativo de la prueba de Papanicolaou fueron: 95.60, 6.60, 96.13 y 5.82%, respectivamente. La sensibilidad, especificidad, valor predictivo positivo y negativo de la colposcopia fueron: 95.98, 33.33, 98.90 y 11.76%, respectivamente. Al hacer la prueba de Kappa el desenlace para el Papanicolaou fue: 0.021 (p = 0.677) y para la colposcopia 0.154 (p = 0.001). CONCLUSIONES: La sensibilidad de la prueba diagnóstica de Papanicolaou y la colposcopia fue alta al igual que el valor predictivo positivo. Es importante analizar las variables que pudieran estar ocasionando la discordancia diagnóstica entre Papanicolaou-colposcopia-histopatología.

Abstract OBJECTIVE: To evaluate the diagnostic concordance between cytology and colposcopy with respect to the histopathological diagnosis of cervical cancer in women from the state of San Luis Potosí who attended a second-level care hospital. MATERIALS AND METHODS: Correlational study performed in a second-level care hospital in the municipality of San Luis Potosí, between 2015 and 2017. Inclusion criteria: to gather three reports of Papanicolaou, colposcopy and histopathology tests based on Richart's classification, to be users of the hospital's colposcopy clinic and to have signed the informed consent. To evaluate the diagnostic concordance, taking the histopathological result as a reference, the Kappa test was performed. RESULTS: We studied 379 patients with a mean age of 34.61 years. The sensitivity, specificity, positive and negative predictive value of the Papanicolaou test were: 95.60, 6.60, 96.13 and 5.82%, respectively. The sensitivity, specificity, positive and negative predictive value of colposcopy were: 95.98, 33.33, 98.90 and 11.76%, respectively. When doing the Kappa test the outcome for Papanicolaou was: 0.021 (p = 0.677) and for colposcopy 0.154 (p = 0.001). CONCLUSIONS: The sensitivity of the Papanicolaou diagnostic test and colposcopy was high as was the positive predictive value. It is important to analyze the variables that could be causing the diagnostic discordance between Papanicolaou-colposcopy-histopathology.

Complex life cycles and density dependence: assessing the contribution of egg mortality to amphibian declines.

In the last decade there has been increasing evidence of amphibian declines from relatively pristine areas. Some declines are hypothesized to be the result of egg mortality caused by factors such as elevated solar UV-B irradiation, chemical pollutants, pathogenic fungi, and climate change. However, the population-level consequences of egg mortality have not been examined explicitly, and may be complicated by density dependence in intervening life-history stages. Here we develop a demographic model for two amphibians with contrasting life-history strategies, Bufo boreas and Ambystoma macrodactylum. We then use the complementary approaches of elasticity and limitation to examine the relationships among stage-specific survival rates, larval-stage density dependence and amphibian population dynamics. Elasticity analyses showed that for a range of density dependence scenarios both species were more sensitive to changes in post-embryonic survival parameters, particularly juvenile survival, than to egg survival, suggesting that mortality of later stages may play an important role in driving declines. Limitation analyses revealed that larval density dependence can dramatically alter the consequences of early mortality, reducing or even reversing the expected population-level effects of egg mortality. Thus, greater focus on later life stages and density dependence is called for to accurately assess how stressors are likely to affect amphibian populations of conservation concern.

Population structure at different minor allele frequency levels.

Inferring population genetic structure from large-scale genotyping of single-nucleotide polymorphisms or variants is an important technique for studying the history and distribution of extant human populations, but it is also a very important tool for adjusting tests of association. However, the structures inferred depend on the minor allele frequency of the variants; this is very important when considering the phenotypic association of rare variants. Using the Genetic Analysis Workshop 18 data set for 142 unrelated individuals, which includes genotypes for many rare variants, we study the following hypothesis: the difference in detected structure is the result of a "scale" effect; that is, rare variants are likely to be shared only locally (smaller scale), while common variants can be spread over longer distances. The result is similar to that of using kernel principal component analysis, as the bandwidth of the kernel is changed. We show how different structures become evident as we consider rare or common variants.

THE DUALITY DIAGRAM IN DATA ANALYSIS: EXAMPLES OF MODERN APPLICATIONS.

Today's data-heavy research environment requires the integration of different sources of information into structured datasets that can not be analyzed as simple matrices. We introduce an old technique, known in the European data analyses circles as the Duality Diagram Approach, put to new uses through the use of a variety of metrics and ways of combining different diagrams together. This issue of the Annals of Applied Statistics contains contemporary examples of how this approach provides solutions to hard problems in data integration. We present here the genesis of the technique and how it can be seen as a precursor of the modern kernel based approaches.

Characterizing the expression of the human olfactory receptor gene family using a novel DNA microarray.

BACKGROUND: Olfactory receptor (OR) genes were discovered more than a decade ago, when Buck and Axel observed that, in rats, certain G-protein coupled receptors are expressed exclusively in the olfactory epithelium. Subsequently, protein sequence similarity was used to identify entire OR gene repertoires of a number of mammalian species, but only in mouse were these predictions followed up by expression studies in olfactory epithelium. To rectify this, we have developed a DNA microarray that contains probes for most predicted human OR loci and used that array to examine OR gene expression profiles in olfactory epithelium tissues from three individuals. RESULTS: We detected expression of 437 (76%) human OR genes in these olfactory epithelia. Interestingly, we detected widespread expression of OR pseudogenes, an observation that may shed light on the mechanism of OR gene choice in the olfactory sensory neurons. To address the hypothesis that OR genes may carry out additional functions, we also characterized the expression of OR genes in a number of non-olfactory tissues. CONCLUSION: While our results corroborate the functional annotation of the majority of predicted human odorant receptors, we find that a large number of putative human OR genes are expressed in non-olfactory tissues, sometimes exclusively so. Our evolutionary analysis of ectopically expressed human OR genes does not lend support to the hypothesis that these genes have alternative functions.