Malaria with neurological involvement in Ugandan children: effect on cognitive ability, academic achievement and behaviour

<p>Abstract</p> <p>Background</p> <p>Malaria is a leading cause of ill health and neuro-disability in children in sub-Saharan Africa. Impaired cognition is a common outcome of malaria with neurological involvement. There is also a possibility that academic achievement may be affected by malaria with neurological involvement given the association between cognitive ability and academic achievement. This study investigated the effect of malaria with neurological involvement on cognitive ability, behaviour and academic achievement.</p> <p>Methods</p> <p>This prospective case-control study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-two children with a history of malaria with neurological involvement were followed up and given assessments for cognitive ability (working memory, reasoning, learning, visual spatial skills and attention), behaviour (internalizing and externalizing problems) and academic achievement (arithmetic, spelling and reading) three months after the illness. Sixty-one community controls recruited from the homes or neighbouring families of the cases were also given the same assessments. Tests scores of the two groups were compared using analysis of covariance with age, sex, level of education, nutritional status and quality of the home environment as covariates. This study was approved by the relevant ethical bodies and informed consent sought from the caregivers.</p> <p>Results</p> <p>Children in the malaria group had more behavioural problems than the community controls for internalizing problems (estimated mean difference = -3.71, 95% confidence interval (CI), = -6.34 to -1.08, p = 0.007). There was marginal evidence of lower attention scores (0.40, CI = -0.05 to 0.86, p = 0.09). However, excluding one child from the analyses who was unable to perform the tests affected the attention scores to borderline significance (0.32, CI, = 0.01 to 0.62, p = 0.05). No significant differences were observed in other cognitive abilities or in academic achievement scores.</p> <p>Conclusion</p> <p>Malaria with neurological involvement affects behaviour, with a minimal effect on attention but no detectable effect on academic achievement at three months post discharge. This study provides evidence that development of cognitive deficits after malaria with neurological involvement could be gradual with less effect observed in the short term compared to the long term.</p

Clinical Features and Serum Biomarkers in HIV Immune Reconstitution Inflammatory Syndrome after Cryptococcal Meningitis: A Prospective Cohort Study

David Boulware and colleagues investigate clinical features in a prospective cohort with AIDS and recent cryptococcal meningitis after initiation of antiretroviral therapy to identify biomarkers for prediction and diagnosis of CM-IRIS (cryptococcal meninigitis-related immune reconstitution inflammatory syndrome)

New methods for finding common insertion sites and co-occurring common insertion sites in transposon- and virus-based genetic screens

Insertional mutagenesis screens in mice are used to identify individual genes that drive tumor formation. In these screens, candidate cancer genes are identified if their genomic location is proximal to a common insertion site (CIS) defined by high rates of transposon or retroviral insertions in a given genomic window. In this article, we describe a new method for defining CISs based on a Poisson distribution, the Poisson Regression Insertion Model, and show that this new method is an improvement over previously described methods. We also describe a modification of the method that can identify pairs and higher orders of co-occurring common insertion sites. We apply these methods to two data sets, one generated in a transposon-based screen for gastrointestinal tract cancer genes and another based on the set of retroviral insertions in the Retroviral Tagged Cancer Gene Database. We show that the new methods identify more relevant candidate genes and candidate gene pairs than found using previous methods. Identification of the biologically relevant set of mutations that occur in a single cell and cause tumor progression will aid in the rational design of single and combinatorial therapies in the upcoming age of personalized cancer therapy

Image analysis and signal extraction from cDNA microarrays

Thesis (Ph. D.)--University of Washington, 2004.The emergence of microarray technology invariably leads to a discussion about data reliability amongst researchers. Many factors impact the accuracy of gene expression data gleaned from microarray experiments. These factors range from noise inherent in the technology platform to variation arising out of experimental design. High level sources of variation encompass deviations that derive from the experimental design while low level sources of variation encompass the noise due to technological errors and biases in the lab. Although so-called high level sources of variation are dominant in microarray data most of the time, these sources can be over-shadowed by data errors at the technological level. That is, although differences in tissue sampled will likely cause most variation, images with artifact noise or dust covering information will taint small, but potentially crucial, sections of the dataset.Because variation due to experimental design is well-covered territory in statistical research, the focus of this dissertation is at the low level of variation. The means to correct for sources of technological variation is not obvious to genomics specialists and statisticians. The research presented here explains the causes for cDNA microarray data variability and methods to account for the low level variance at two points: (1) image analysis and (2) signal extraction. The image analysis takes a TIFF image and performs grid alignment, spot detection, background estimation, flagging and outputs the information to a text file. The image analysis routine to be outlined herein is automated, reproducible, and robust.Signal extraction involves the modeling of spot pixel data to describe the overall spot intensity level and a measure of spot reliability while incorporating both red and green channels from the experiment. The spot quality measure will be spot-specific and continuous such that each data point in a set of experiments has an assigned data reliability weight. This quality measure can then be used to downweight low quality data in a regression-type analysis. In this way, spots that are tainted with artifact noise, and therefore have inaccurate expression levels, do not mar downstream analysis. A spot quality measure is also better than a flag, as summarily removing flagged data results in missing data problems. But using a spot quality weight does not result in missing data and may improve efficiency in test statistics.A wide variety of methods to describe spot level quality estimates were investigated. The examination included several ways to incorporate spatial structure between pixel pairs. Semi-parametric methods to describe the variance of spots were not estimable for this data structure in the absence of spot replication. If updates to microarray technology protocols include spot replication, then semi-parametric measures can be revisited. Smoothers to describe correlation required a priori knowledge of the correlation size in order to adjust bandwidths resulting in a circularity problem. Ultimately, a fully parametric and a fully non-parametric estimate to describe quality are introduced and shown to be feasible for a data reliability model

Proportion statistics to detect differentially expressed genes: a comparison with log-ratio statistics

Abstract Background In genetic transcription research, gene expression is typically reported in a test sample relative to a reference sample. Laboratory assays that measure gene expression levels, from Q-RT-PCR to microarrays to RNA-Seq experiments, will compare two samples to the same genetic sequence of interest. Standard practice is to use the log2-ratio as the measure of relative expression. There are drawbacks to using this measurement, including unstable ratios when the denominator is small. This paper suggests an alternative estimate based on a proportion that is just as simple to calculate, just as intuitive, with the added benefit of greater numerical stability. Results Analysis of two groups of mice measured with 16 cDNA microarrays found similar results between the previously used methods and our proposed methods. In a study of liver and kidney samples measured with RNA-Seq, we found that proportion statistics could detect additional differentially expressed genes usually classified as missing by ratio statistics. Additionally, simulations demonstrated that one of our proposed proportion-based test statistics was robust to deviations from distributional assumptions where all other methods examined were not. Conclusions To measure relative expression between two samples, the proportion estimates that we propose yield equivalent results to the log2-ratio under most circumstances and better results than the log2-ratio when expression values are close to zero.</p

KIR reconstitution is altered by T cells in the graft and correlates with clinical outcomes after unrelated donor transplantation

Although unrelated hematopoietic cell transplantation (HCT) is curative for many hematologic malignancies, complications and relapse remain challenging obstacles. Natural killer (NK) cells, which recover quickly after transplantation, produce cytokines and express killer immunoglobulin-like receptors (KIRs) that regulate their cytotoxicity. Some clinical trials based on a KIR ligand mismatch strategy are associated with less relapse and increased survival, but results are mixed. We hypothesized that T cells in the graft may affect NK cell function and KIR expression after unrelated transplantation and that these differences correlate with clinical outcomes. NK cell function was evaluated using 77 paired samples from the National Marrow Donor Program Research Repository. Recipient NK cells at 100 days after both unmanipulated bone marrow (UBM) and T-cell depleted (TCD) transplants were compared with NK cells from their healthy donors. NK cells expressed fewer KIRs and produced more interferon γ (IFN-γ) after UBM compared to TCD transplants. Multivariate models showed that increased NK cell IFN-γ production correlated with more acute graft-versus-host disease (GVHD), and decreased KIR expression correlated with inferior survival. These results support the notion that T cells in the graft affect NK cell reconstitution in vivo. Understanding these mechanisms may result in strategies to improve clinical outcomes from unrelated HCT