Combining gene expression, demographic and clinical data in modeling disease: a case study of bipolar disorder and schizophrenia

<p>Abstract</p> <p>Background</p> <p>This paper presents a retrospective statistical study on the newly-released data set by the Stanley Neuropathology Consortium on gene expression in bipolar disorder and schizophrenia. This data set contains gene expression data as well as limited demographic and clinical data for each subject. Previous studies using statistical classification or machine learning algorithms have focused on gene expression data only. The present paper investigates if such techniques can benefit from including demographic and clinical data.</p> <p>Results</p> <p>We compare six classification algorithms: support vector machines (SVMs), nearest shrunken centroids, decision trees, ensemble of voters, naïve Bayes, and nearest neighbor. SVMs outperform the other algorithms. Using expression data only, they yield an area under the ROC curve of 0.92 for bipolar disorder versus control, and 0.91 for schizophrenia versus control. By including demographic and clinical data, classification performance improves to 0.97 and 0.94 respectively.</p> <p>Conclusion</p> <p>This paper demonstrates that SVMs can distinguish bipolar disorder and schizophrenia from normal control at a very high rate. Moreover, it shows that classification performance improves by including demographic and clinical data. We also found that some variables in this data set, such as alcohol and drug use, are strongly associated to the diseases. These variables may affect gene expression and make it more difficult to identify genes that are directly associated to the diseases. Stratification can correct for such variables, but we show that this reduces the power of the statistical methods.</p

PEGylated-nanoliposomal clusterin for amyloidogenic light chain-induced endothelial dysfunction

Light chain (AL) amyloidosis is a disease associated with significant morbidity and mortality arising from multi-organ injury induced by amyloidogenic light chain proteins (LC). There is no available treatment to reverse the toxicity of LC. We previously showed that chaperone glycoprotein clusterin (CLU) and nanoliposomes (NL), separately, restore human microvascular endothelial function impaired by LC. In this work, we aim to prepare PEGylated-nanoliposomal clusterin (NL-CLU) formulations that could allow combined benefit against LC while potentially enabling efficient delivery to microvascular tissue, and test efficacy on human arteriole endothelial function. NL-CLU was prepared by a conjugation reaction between the carboxylated surface of NL and the primary amines of the CLU protein. NL were made of phosphatidylcholine (PC), cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG 2000 carboxylic acid) at 70:25:5mol%. The protective effect of NL-CLU was tested by measuring the dilation response to acetylcholine and papaverine in human adipose arterioles exposed to LC. LC treatment significantly reduced the dilation response to acetylcholine and papaverine; co-treatment of LC with PEGylated-nanoliposomal CLU or free CLU restored the dilator response. NL-CLU is a feasible and promising approach to reverse LC-induced endothelial damage.College of Pharmacy-Glendale, Midwestern UniversityOpen access article.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function

We have identified a lethal phenotype characterized by sudden infant death (from cardiac and respiratory arrest) with dysgenesis of the testes in males [Online Mendelian Inheritance in Man (OMIM) accession no. 608800]. Twenty-one affected individuals with this autosomal recessive syndrome were ascertained in nine separate sibships among the Old Order Amish. High-density single-nucleotide polymorphism (SNP) genotyping arrays containing 11,555 single-nucleotide polymorphisms evenly distributed across the human genome were used to map the disease locus. A genome-wide autozygosity scan localized the disease gene to a 3.6-Mb interval on chromosome 6q22.1-q22.31. This interval contained 27 genes, including two testis-specific Y-like genes (TSPYL and TSPYL4) of unknown function. Sequence analysis of the TSPYL gene in affected individuals identified a homozygous frameshift mutation (457_458insG) at codon 153, resulting in truncation of translation at codon 169. Truncation leads to loss of a peptide domain with strong homology to the nucleosome assembly protein family. GFP-fusion expression constructs were constructed and illustrated loss of nuclear localization of truncated TSPYL, suggesting loss of a nuclear localization patch in addition to loss of the nucleosome assembly domain. These results shed light on the pathogenesis of a disorder of sexual differentiation and brainstem-mediated sudden death, as well as give insight into a mechanism of transcriptional regulation

Study on essential derivation in maize: III. Selection and evaluation of a panel of single nucleotide polymorphism loci for use in European and North American germplasm

Pairwise distance data for maize (Zea mays L.) inbred lines generated using sets of single nucleotide polymorphisms (SNPs) selected from a 50k Infinium array were compared with pairwise distances generated using a set of 163 simple sequence repeat (SSR) loci previously identified to help determine essentially derived variety (EDV) status (UPOV, 1991). Final comparisons were made using 26,874 SNPs after discarding SNPs with insufficient data quality or vulnerability to ascertainment bias. Inbred lines developed in the United States or in western Europe that had been previously published to establish SSR-based thresholds provided the means to determine equivalent SNP-based protocols. Use of 3072 SNPs selected to provide even genomic coverage according to genetic and physical maps provided robust, precise, high discrimination among inbred lines with consistent zonal classification with up to 20% missing data. Comparisons of intercepts and slopes for SSR and SNP inbred pairwise distance data translated the 82% SSR green-orange similarity threshold to 91% using SNPs and the 90% SSR orange-red threshold to 95% using SNPs. Information required to conduct analyses using these 3072 SNPS is presented