Allowing for heterogeneity in the decomposition of measures of inequality in health

This paper shows how recently developed regression-based methods for the decomposition ofhealth inequality can be extended to incorporate heterogeneity in the responses of health to the explanatory variables. We illustrate our method with an application to the GHQ measure of psychological well-being taken from the British Household Panel Survey. The results suggest that there is an important degree of heterogeneity in the association of health to explanatory variables across birth cohorts and genders which, in turn, accounts for a substantial percentage of the inequality in observed health.

Genome-wide association study of major recurrent depression in the U.K. population.

OBJECTIVE: Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. METHOD: Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. RESULTS: Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. CONCLUSIONS: This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

Measurement and explanation of socioeconomic inequality in health with longitudinal data

This paper presents a method for the measurement of changes in health inequality and income-related health inequality over time in a population.For pure health inequality (as measured by the Gini coefficient) andincome-related health inequality (as measured by the concentration index),we show how measures derived from longitudinal data can be related tocross section Gini and concentration indices that have been typicallyreported in the literature to date, along with measures of health mobilityinspired by the literature on income mobility. We also show how thesemeasures of mobility can be usefully decomposed into the contributions ofdifferent covariates. We apply these methods to investigate the degree ofincome-related mobility in the GHQ measure of psychological well-being inthe first nine waves of the British Household Panel Survey (BHPS). Thisreveals that dynamics increase the absolute value of the concentrationindex of GHQ on income by 10%.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

The importance of individual heterogeneity in the decomposition of measures of socioeconomic inequality in health: An approach based on quantile regression

This paper shows how recently developed regression-based methods for thedecomposition of health inequality can be extended to incorporateindividual heterogeneity in the responses of health to the explanatoryvariables. We illustrate our method with an application to the CanadianNPHS of 1994. Our strategy for the estimation of heterogeneous responsesis based on the quantile regression model. The results suggest that thereis an important degree of heterogeneity in the association of health toexplanatory variables which, in turn, accounts for a substantial percentageof inequality in observed health. A particularly interesting finding isthat the marginal response of health to income is zero for healthyindividuals but positive and significant for unhealthy individuals. Theheterogeneity in the income response reduces both overall health inequalityand income related health inequality.

Três métodos de cálculo do DRIS para avaliar o potencial de resposta à adubação de árvores de eucalipto

O objetivo deste trabalho foi testar o efeito de três métodos de cálculo do DRIS no diagnóstico nutricional de árvores de eucalipto, resultantes da interpretação dos índices pelo método do potencial de resposta à adubação. Para tanto, foram obtidas informações dos teores dos nutrientes em quatro órgãos (folhas, galhos, casca e lenho) de 1.986 árvores de híbridos de Eucalyptus grandi s x E. urophylla, coletadas, entre os anos de 1988 a 1994, de talhões comerciais pertencentes à Aracruz Celulose S.A. e cultivados no Espírito Santo e no sul da Bahia, utilizando os métodos de Jones, Elwali & Gascho e da Faixa de Beaufils. Dentre os métodos testados, o das Faixas de Beaufils mostrou-se o mais conservador e muito semelhante ao método de Elwali & Gascho quanto à freqüência de nutrientes considerados deficientes. O método de Jones foi o que apresentou maior freqüência de nutrientes considerados deficientes, não se tendo observado, entretanto, efeito da seleção das relações no cálculo dos índices DRIS sobre a freqüência de nutrientes considerados deficientes. A utilização do critério do potencial de resposta à adubação para a interpretação dos índices DRIS conduz a resultados semelhantes entre os métodos, de forma que qualquer deles poderia vir a ser utilizado com relativa segurança, sem grandes conseqüências no diagnóstico nutricional da maioria dos nutrientes e das situações.

Valores de referência para macronutrientes em eucalipto obtidos pelos métodos DRIS e chance matemática

Informações de 1.213 árvores de plantios comerciais foram obtidas, entre os anos de 1988 a 1994, de híbridos de Eucalyptus grandis x E. urophylla, da Aracruz Celulose S.A., cultivados no estado do Espírito Santo, Brasil. Os resultados da produtividade e concentração dos macronutrientes em quatro órgãos das árvores foram utilizados na obtenção dos valores de referência para a concentração dos nutrientes, pelos métodos da Chance Matemática e do DRIS. Empregou-se, no cálculo dos índices DRIS, a fórmula de Jones (1981), a divisão da população-base em estratos de idade e a seleção das relações entre os nutrientes pelo teste F. O nível crítico dos nutrientes foi atingido pelo DRIS por meio de dois critérios: pela concentração média dos nutrientes nos talhões nutricionalmente balanceados e produtivos (NCO) e pelo critério gráfico (NCG). O primeiro critério mostrou-se mais promissor, inclusive em relação ao método da Chance Matemática, o qual foi adequado principalmente para a determinação de faixa ótima que poderia ser adotada como referência para o limite inferior e o superior de árvores com níveis adequados dos nutrientes.

Mutant huntingtin's effects on striatal gene expression in mice recapitulate changes observed in human Huntington's disease brain and do not differ with mutant huntingtin length or wild-type huntingtin dosage.

To test the hypotheses that mutant huntingtin protein length and wild-type huntingtin dosage have important effects on disease-related transcriptional dysfunction, we compared the changes in mRNA in seven genetic mouse models of Huntington's disease (HD) and postmortem human HD caudate. Transgenic models expressing short N-terminal fragments of mutant huntingtin (R6/1 and R6/2 mice) exhibited the most rapid effects on gene expression, consistent with previous studies. Although changes in the brains of knock-in and full-length transgenic models of HD took longer to appear, 15- and 22-month CHL2(Q150/Q150), 18-month Hdh(Q92/Q92) and 2-year-old YAC128 animals also exhibited significant HD-like mRNA signatures. Whereas it was expected that the expression of full-length huntingtin transprotein might result in unique gene expression changes compared with those caused by the expression of an N-terminal huntingtin fragment, no discernable differences between full-length and fragment models were detected. In addition, very high correlations between the signatures of mice expressing normal levels of wild-type huntingtin and mice in which the wild-type protein is absent suggest a limited effect of the wild-type protein to change basal gene expression or to influence the qualitative disease-related effect of mutant huntingtin. The combined analysis of mouse and human HD transcriptomes provides important temporal and mechanistic insights into the process by which mutant huntingtin kills striatal neurons. In addition, the discovery that several available lines of HD mice faithfully recapitulate the gene expression signature of the human disorder provides a novel aspect of validation with respect to their use in preclinical therapeutic trials.

Les interventions de soutien direct auprès des aidants naturels réduisent leur détresse psychologique: revue Cochrane pour le praticien.

Cet article présente les résultats de la revue systématique: Candy B, Jones L, Drake R, Leurent B, King M. Interventions for supporting informal caregivers of patients in the terminal phase of a disease. Cochrane Database Syst Rev. 2011 Jun 15;(6):CD007617. PMID: 21678368. Contexte : Les aidants naturels sont des personnes bénévoles qui dispensent des soins physiques et, ou un soutien émotionnel à l'un(e) de leur proche ou ami(e). Ceci peut générer un stress intense tant physique que psychique. Des interventions visant principalement à augmenter la qualité de vie et à soutenir la vie affective des aidants naturels ont été développées. Cette revue systématique évalue l'effet de ces interventions sur la santé physique et psychique des aidants naturels de patients en phase terminale. [Auteurs]

The implications of alternative splicing in the ENCODE protein complement.

Alternative premessenger RNA splicing enables genes to generate more than one gene product. Splicing events that occur within protein coding regions have the potential to alter the biological function of the expressed protein and even to create new protein functions. Alternative splicing has been suggested as one explanation for the discrepancy between the number of human genes and functional complexity. Here, we carry out a detailed study of the alternatively spliced gene products annotated in the ENCODE pilot project. We find that alternative splicing in human genes is more frequent than has commonly been suggested, and we demonstrate that many of the potential alternative gene products will have markedly different structure and function from their constitutively spliced counterparts. For the vast majority of these alternative isoforms, little evidence exists to suggest they have a role as functional proteins, and it seems unlikely that the spectrum of conventional enzymatic or structural functions can be substantially extended through alternative splicing.

Extent and patterns of MGMT promoter methylation in glioblastoma- and respective glioblastoma-derived spheres.

Purpose: Quantitative methylation-specific tests suggest that not all cells in a glioblastoma with detectable promoter methylation of the O6-methylguanine DNA methyltransferase (MGMT) gene carry a methylated MGMT allele. This observation may indicate cell subpopulations with distinct MGMT status, raising the question of the clinically relevant cutoff of MGMT methylation therapy. Epigenetic silencing of the MGMT gene by promoter methylation blunts repair of O6-methyl guanine and has been shown to be a predictive factor for benefit from alkylating agent therapy in glioblastoma. Experimental Design: Ten paired samples of glioblastoma and respective glioblastoma-derived spheres (GS), cultured under stem cell conditions, were analyzed for the degree and pattern of MGMT promoter methylation by methylation-specific clone sequencing, MGMT gene dosage, chromatin status, and respective effects on MGMT expression and MGMT activity. Results: In glioblastoma, MGMT-methylated alleles ranged from 10% to 90%. In contrast, methylated alleles were highly enriched (100% of clones) in respective GS, even when 2 MGMT alleles were present, with 1 exception (<50%). The CpG methylation patterns were characteristic for each glioblastoma exhibiting 25% to 90% methylated CpGs of 28 sites interrogated. Furthermore, MGMT promoter methylation was associated with a nonpermissive chromatin status in accordance with very low MGMT transcript levels and undetectable MGMT activity. Conclusions: In MGMT-methylated glioblastoma, MGMT promoter methylation is highly enriched in GS that supposedly comprise glioma-initiating cells. Thus, even a low percentage of MGMT methylation measured in a glioblastoma sample may be relevant and predict benefit from an alkylating agent therapy. Clin Cancer Res; 17(2); 255-66. (C)2010 AACR.