Identification of gene pathways implicated in Alzheimer's disease using longitudinal imaging phenotypes with sparse regression

We present a new method for the detection of gene pathways associated with a multivariate quantitative trait, and use it to identify causal pathways associated with an imaging endophenotype characteristic of longitudinal structural change in the brains of patients with Alzheimer's disease (AD). Our method, known as pathways sparse reduced-rank regression (PsRRR), uses group lasso penalised regression to jointly model the effects of genome-wide single nucleotide polymorphisms (SNPs), grouped into functional pathways using prior knowledge of gene-gene interactions. Pathways are ranked in order of importance using a resampling strategy that exploits finite sample variability. Our application study uses whole genome scans and MR images from 464 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. 66,182 SNPs are mapped to 185 gene pathways from the KEGG pathways database. Voxel-wise imaging signatures characteristic of AD are obtained by analysing 3D patterns of structural change at 6, 12 and 24 months relative to baseline. High-ranking, AD endophenotype-associated pathways in our study include those describing chemokine, Jak-stat and insulin signalling pathways, and tight junction interactions. All of these have been previously implicated in AD biology. In a secondary analysis, we investigate SNPs and genes that may be driving pathway selection, and identify a number of previously validated AD genes including CR1, APOE and TOMM40

Treatment of Deep Vein Thrombosis with Continuous IV Infusion of LMWH: A Retrospective Study in 32 Children

Thirty-two consecutive children aged 0–18 years with VTE treated with LMWH administered as a continuous infusion (CI) were identified at the Children's University Hospital Brno. The treatment led to at least partial resolution of the thrombus within two weeks in 85% of patients. There were no adverse events or increased bleeding reported in any patients. No recurrences were observed during a followup period of 6 months. Although continuous infusion should not replace subcutaneous (SC) administration of LMWH, CI appeared to be safe and efficient and may provide an alternate method of administering LMWH in a subset of the paediatric population where SC administration may not be feasible. Further prospective studies are needed to support the promising findings of our pilot clinical observation

Supervised, Multivariate, Whole-Brain Reduction Did Not Help to Achieve High Classification Performance in Schizophrenia Research

We examined how penalized linear discriminant analysis with resampling, which is a supervised, multivariate, whole-brain reduction technique, can help schizophrenia diagnostics and research. In an experiment with magnetic resonance brain images of 52 first-episode schizophrenia patients and 52 healthy controls, this method allowed us to select brain areas relevant to schizophrenia, such as the left prefrontal cortex, the anterior cingulum, the right anterior insula, the thalamus and the hippocampus. Nevertheless, the classification performance based on such reduced data was not significantly better than the classification of data reduced by mass univariate selection using a t-test or unsupervised multivariate reduction using principal component analysis. Moreover, we found no important influence of the type of imaging features, namely local deformations or grey matter volumes, and the classification method, specifically linear discriminant analysis or linear support vector machines, on the classification results. However, we ascertained significant effect of a cross-validation setting on classification performance as classification results were overestimated even though the resampling was performed during the selection of brain imaging features. Therefore, it is critically important to perform cross-validation in all steps of the analysis (not only during classification) in case there is no external validation set to avoid optimistically biasing the results of classification studies

Addenbrooke’s Cognitive Examination and Individual Domain Cut-Off Scores for Discriminating between Different Cognitive Subtypes of Parkinson’s Disease

Objective. The main aim of this study was to verify the sensitivity and specificity of Addenbrooke’s Cognitive Examination-Revised (ACE-R) in discriminating between Parkinson’s disease (PD) with normal cognition (PD-NC) and PD with mild cognitive impairment (PD-MCI) and between PD-MCI and PD with dementia (PD-D). We also evaluated how ACE-R correlates with neuropsychological cognitive tests in PD. Methods. We examined three age-matched groups of PD patients diagnosed according to the Movement Disorder Society Task Force criteria: PD-NC, PD-MCI, and PD-D. ROC analysis was used to establish specific cut-off scores of ACE-R and its domains. Correlation analyses were performed between ACE-R and its subtests with relevant neuropsychological tests. Results. Statistically significant differences between groups were demonstrated in global ACE-R scores and subscores, except in the language domain. ACE-R cut-off score of 88.5 points discriminated best between PD-MCI and PD-NC (sensitivity 0.68, specificity 0.91); ACE-R of 82.5 points distinguished best between PD-MCI and PD-D (sensitivity 0.70, specificity 0.73). The verbal fluency domain of ACE-R demonstrated the best discrimination between PD-NC and PD-MCI (cut-off score 11.5; sensitivity 0.70, specificity 0.73) while the orientation/attention subscore was best between PD-MCI and PD-D (cut-off score 15.5; sensitivity 0.90, specificity 0.97). ACE-R scores except for ACE-R language correlated with specific cognitive tests of interest

Sparse reduced-rank regression detects genetic associations with voxel-wise longitudinal phenotypes in Alzheimer's disease

Scanning the entire genome in search of variants related to imaging phenotypes holds great promise in elucidating the genetic etiology of neurodegenerative disorders. Here we discuss the application of a penalized multivariate model, sparse reduced-rank regression (sRRR), for the genome-wide detection of markers associated with voxel-wise longitudinal changes in the brain caused by Alzheimer’s disease (AD). Using a sample from the Alzheimer’s Disease Neuroimaging Initiative database, we performed three separate studies that each compared two groups of individuals to identify genes associated with disease development and progression. For each comparison we took a two-step approach: initially, using penalized linear discriminant analysis, we identified voxels that provide an imaging signature of the disease with high classification accuracy; then we used this multivariate biomarker as a phenotype in a genome-wide association study, carried out using sRRR. The genetic markers were ranked in order of importance of association to the phenotypes using a data re-sampling approach. Our findings confirmed the key role of the APOE and TOMM40 genes but also highlighted some novel potential associations with AD