Active Selection of Classification Features

Some data analysis applications comprise datasets, where explanatory variables are expensive or tedious to acquire, but auxiliary data are readily available and might help to construct an insightful training set. An example is neuroimaging research on mental disorders, specifically learning a diagnosis/prognosis model based on variables derived from expensive Magnetic Resonance Imaging (MRI) scans, which often requires large sample sizes. Auxiliary data, such as demographics, might help in selecting a smaller sample that comprises the individuals with the most informative MRI scans. In active learning literature, this problem has not yet been studied, despite promising results in related problem settings that concern the selection of instances or instance-feature pairs. Therefore, we formulate this complementary problem of Active Selection of Classification Features (ASCF): Given a primary task, which requires to learn a model f: x-> y to explain/predict the relationship between an expensive-to-acquire set of variables x and a class label y. Then, the ASCF-task is to use a set of readily available selection variables z to select these instances, that will improve the primary task's performance most when acquiring their expensive features z and including them to the primary training set. We propose two utility-based approaches for this problem, and evaluate their performance on three public real-world benchmark datasets. In addition, we illustrate the use of these approaches to efficiently acquire MRI scans in the context of neuroimaging research on mental disorders, based on a simulated study design with real MRI data.Comment: Accepted for publication at the 19th Intelligent Data Analysis Symposium, 2021. The final authenticated publication will be made available online at springer.co

Marketing authorization procedures for advanced cancer drugs: exploring the views of patients, oncologists, healthcare decision makers and citizens in France

International audienceBackground. The past decades have seen advances in cancer treatments in terms of toxicity and side effects but progress in the treatment of advanced cancer has been modest. New drugs have emerged improving progression free survival but with little impact on overall survival, raising questions about the criteria on which to base decisions to grant marketing authorizations and about the authorization procedure itself. For decisions to be fair, transparent and accountable, it is necessary to consider the views of those with relevant expertise and experience. Methods. We conducted a Q-study to explore the views of a range of stakeholders in France, involving: 54 patients (18 months after diagnosis); 50 members of the general population; 27 oncologists; 19 healthcare decision makers; and 2 individuals from the pharmaceutical industry. Results. Three viewpoints emerged, focussing on different dimensions entitled: 1) ‘Quality of life (QoL), opportunity cost and participative democracy’; 2)‘QoL and patient-centeredness’; and 3) ‘Length of life’. Respondents from all groups were associated with each viewpoint, except for healthcare decision makers, who were only associated with the first one. Conclusion. Our results highlight plurality in the views of stakeholders, emphasize the need for transparency in decision making processes, and illustrate the importance of a re-evaluation of treatments for all 3 viewpoints. In the context of advanced cancer, our results suggest that QoL should be more prominent amongst authorization criteria, as it is a concern for 2 of the 3 viewpoints

Genetic Influences on the Development of Cerebral Cortical Thickness During Childhood and Adolescence in a Dutch Longitudinal Twin Sample:The Brainscale Study

Previous studies have demonstrated that cortical thickness (CT) is under strong genetic control across the life span. However, little is known about genetic influences that cause changes in cortical thickness (ΔCT) during brain development. We obtained 482 longitudinal MRI scans at ages 9, 12, and 17 years from 215 twins and applied structural equation modeling to estimate genetic influences on (1) cortical thickness between regions and across time, and (2) changes in cortical thickness between ages. Although cortical thickness is largely mediated by the same genetic factor throughout late childhood and adolescence, we found evidence for influences of distinct genetic factors on regions across space and time. In addition, we found genetic influences for cortical thinning during adolescence that is mostly due to fluctuating influences from the same genetic factor, with evidence of local influences from a second emerging genetic factor. This fluctuating core genetic factor and emerging novel genetic factor might be implicated in the rapid cognitive and behavioral development during childhood and adolescence, and could potentially be targets for investigation into the manifestation of psychiatric disorders that have their origin in childhood and adolescence

The consequences of tobacco tax on household health and fi nances in rich and poor smokers in China: an extended cost-eff ectiveness analysis

Background In China, there are more than 300 million male smokers. Tobacco taxation reduces smoking-related premature deaths and increases government revenues, but has been criticised for disproportionately aff ecting poorer people. We assess the distributional consequences (across diff erent wealth quintiles) of a specifi c excise tax on cigarettes in China in terms of both fi nancial and health outcomes. Methods We use extended cost-eff ectiveness analysis methods to estimate, across income quintiles, the health benefi ts (years of life gained), the additional tax revenues raised, the net fi nancial consequences for households, and the fi nancial risk protection provided to households, that would be caused by a 50% increase in tobacco price through excise tax fully passed onto tobacco consumers. For our modelling analysis, we used plausible values for key parameters, including an average price elasticity of demand for tobacco of –0·38, which is assumed to vary from –0·64 in the poorest quintile to –0·12 in the richest, and we considered only the male population, which constitutes the overwhelming majority of smokers in China. Findings Our modelling analysis showed that a 50% increase in tobacco price through excise tax would lead to 231 million years of life gained (95% uncertainty range 194–268 million) over 50 years (a third of which would be gained in the lowest income quintile), a gain of US$703 billion ($616–781 billion) of additional tax revenues from the excise tax (14% of which would come from the lowest income quintile, compared with 24% from the highest income quintile). The excise tax would increase overall household expenditures on tobacco by $376 billion ($232–505 billion), but decrease these expenditures by $21 billion (–$83 to $5 billion) in the lowest income quintile, and would reduce expenditures on tobacco-related disease by$24·0 billion ($17·3–26·3 billion, 28 income quintile). Finally, it would provide fi nancial risk protection worth$1·8 billion ($1·2–2·3 billion), mainly concentrated (74%) in the lowest income quintile. Interpretation Increased tobacco taxation can be a pro-poor policy instrument that brings substantial health and fi nancial benefi ts to households in China

Contributing factors to advanced brain aging in depression and anxiety disorders

Depression and anxiety are common and often comorbid mental health disorders that represent risk factors for aging-related conditions. Brain aging has shown to be more advanced in patients with major depressive disorder (MDD). Here, we extend prior work by investigating multivariate brain aging in patients with MDD, anxiety disorders, or both, and examine which factors contribute to older-appearing brains. Adults aged 18–57 years from the Netherlands Study of Depression and Anxiety underwent structural MRI. A pretrained brain-age prediction model based on >2000 samples from the ENIGMA consortium was applied to obtain brain-predicted age differences (brain PAD, predicted brain age minus chronological age) in 65 controls and 220 patients with current MDD and/or anxiety. Brain-PAD estimates were associated with clinical, somatic, lifestyle, and biological factors. After correcting for antidepressant use, brain PAD was significantly higher in MDD (+2.78 years, Cohen’s d = 0.25, 95% CI −0.10-0.60) and anxiety patients (+2.91 years, Cohen’s d = 0.27, 95% CI −0.08-0.61), compared with controls. There were no significant associations with lifestyle or biological stress systems. A multivariable model indicated unique contributions of higher severity of somatic depression symptoms (b = 4.21 years per unit increase on average sum score) and antidepressant use (−2.53 years) to brain PAD. Advanced brain aging in patients with MDD and anxiety was most strongly associated with somatic depressive symptomatology. We also present clinically relevant evidence for a potential neuroprotective antidepressant effect on the brain-PAD metric that requires follow-up in future research

Understanding hallucinations in probable Alzheimer's disease:Very low prevalence rates in a tertiary memory clinic

Introduction: Averaging at 13.4%, current literature reports widely varying prevalence rates of hallucinations in patients with probable Alzheimer's disease (AD), and is still inconclusive on contributive factors to hallucinations in AD. Methods: This study assessed prevalence, associated factors and clinical characteristics of hallucinations in 1227 patients with probable AD, derived from a tertiary memory clinic specialized in early diagnosis of dementia. Hallucinations were assessed with the Neuropsychiatric Inventory. Results: Hallucination prevalence was very low, with only 4.5% (n = 55/1227) affected patients. Hallucinations were mostly visual (n = 40/55) or auditory (n = 12/55). Comorbid delusions were present in over one-third of cases (n = 23/55). Hallucinations were associated with increased dementia severity, neuropsychiatric symptoms, and a lifetime history of hallucination-evoking disease (such as depression and sensory impairment), but not with age or gender. Discussion: In the largest sample thus far, we report a low prevalence of hallucinations in probable AD patients, comparable to rates in non-demented elderly. Our results suggest that hallucinations are uncommon in early stage AD. Clinicians that encounter hallucinations in patients with early AD should be sensitive to hallucination-evoking comorbidity

Changes in anti-viral effectiveness of interferon after dose reduction in chronic hepatitis c patients: a case control study

BACKGROUND: High dose interferon induction treatment of hepatitis C viral infection blocks viral production over 95%. Since dose reduction is often performed due to clinical considerations, the effect of dose reduction on hepatitis C virus kinetics was studied. METHODS: A new model that allowed longitudinal changes in the parameters of viral dynamics was used in a group of genotype-1 patients (N = 15) with dose reduction from 10 to 3 million units of interferon daily in combination with ribavirin, in comparison to a control group (N = 9) with no dose reduction. RESULTS: Dose reduction gave rise to a complex viral kinetic pattern, which could be only explained by a decrease in interferon effectiveness in blocking virion production. The benefit of the rapid initial viral decline following the high induction dose is lost after dose reduction. In addition, in some patients also the second phase viral decline slope, which is highly predictive of success of treatment, was impaired by the dose reduction resulting in smaller percentage of viral clearance in the dose reduction group. CONCLUSIONS: These findings, while explaining the failure of many induction schedules, suggest that for genotype-1 patients induction therapy should be continued till HCVRNA negativity in serum in order to increase the sustained response rate for chronic hepatitis C

Multi-site genetic analysis of diffusion images and voxelwise heritability analysis : a pilot project of the ENIGMA–DTI working group

The ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) Consortium was set up to analyze brain measures and genotypes from multiple sites across the world to improve the power to detect genetic variants that influence the brain. Diffusion tensor imaging (DTI) yields quantitative measures sensitive to brain development and degeneration, and some common genetic variants may be associated with white matter integrity or connectivity. DTI measures, such as the fractional anisotropy (FA) of water diffusion, may be useful for identifying genetic variants that influence brain microstructure. However, genome-wide association studies (GWAS) require large populations to obtain sufficient power to detect and replicate significant effects, motivating a multi-site consortium effort. As part of an ENIGMA–DTI working group, we analyzed high-resolution FA images from multiple imaging sites across North America, Australia, and Europe, to address the challenge of harmonizing imaging data collected at multiple sites. Four hundred images of healthy adults aged 18–85 from four sites were used to create a template and corresponding skeletonized FA image as a common reference space. Using twin and pedigree samples of different ethnicities, we used our common template to evaluate the heritability of tract-derived FA measures. We show that our template is reliable for integrating multiple datasets by combining results through meta-analysis and unifying the data through exploratory mega-analyses. Our results may help prioritize regions of the FA map that are consistently influenced by additive genetic factors for future genetic discovery studies. Protocols and templates are publicly available at (http://enigma.loni.ucla.edu/ongoing/dti-working-group/)

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an emerging public health problem without effective therapies. Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into bioactive epoxyeicosatrienoic acids (EETs), which have potent anti-inflammatory and protective effects. However, the functional relevance of the CYP epoxyeicosanoid metabolism pathway in the pathogenesis of NASH remains poorly understood. Our studies demonstrate that both mice with methionine-choline deficient (MCD) diet-induced NASH and humans with biopsy-confirmed NASH exhibited significantly higher free EET concentrations compared to healthy controls. Targeted disruption of Ephx2 (the gene encoding for soluble epoxide hydrolase) in mice further increased EET levels and significantly attenuated MCD diet-induced hepatic steatosis, inflammation and injury, as well as high fat diet-induced adipose tissue inflammation, systemic glucose intolerance and hepatic steatosis. Collectively, these findings suggest that dysregulation of the CYP epoxyeicosanoid pathway is a key pathological consequence of NASH in vivo, and promoting the anti-inflammatory and protective effects of EETs warrants further investigation as a novel therapeutic strategy for NASH

Disordered clusters of Bak dimers rupture mitochondria during apoptosis

During apoptosis, Bak and Bax undergo major conformational change and form symmetric dimers that coalesce to perforate the mitochondrial outer membrane via an unknown mechanism. We have employed cysteine labelling and linkage analysis to the full length of Bak in mitochondria. This comprehensive survey showed that in each Bak dimer the N-termini are fully solvent-exposed and mobile, the core is highly structured, and the C-termini are flexible but restrained by their contact with the membrane. Dimer-dimer interactions were more labile than the BH3:groove interaction within dimers, suggesting there is no extensive protein interface between dimers. In addition, linkage in the mobile Bak N-terminus (V61C) specifically quantified association between dimers, allowing mathematical simulations of dimer arrangement. Together, our data show that Bak dimers form disordered clusters to generate lipidic pores. These findings provide a molecular explanation for the observed structural heterogeneity of the apoptotic pore