Promising Metabolite Profiles in the Plasma and CSF of Early Clinical Parkinson's Disease

Parkinson's disease (PD) shows high heterogeneity with regard to the underlying molecular pathogenesis involving multiple pathways and mechanisms. Diagnosis is still challenging and rests entirely on clinical features. Thus, there is an urgent need for robust diagnostic biofluid markers. Untargeted metabolomics allows establishing low-molecular compound biomarkers in a wide range of complex diseases by the measurement of various molecular classes in biofluids such as blood plasma, serum, and cerebrospinal fluid (CSF). Here, we applied untargeted high-resolution mass spectrometry to determine plasma and CSF metabolite profiles. We semiquantitatively determined small-molecule levels (≤1.5 kDa) in the plasma and CSF from early PD patients (disease duration 0-4 years; n = 80 and 40, respectively), and sex- and age-matched controls (n = 76 and 38, respectively). We performed statistical analyses utilizing partial least square and random forest analysis with a 70/30 training and testing split approach, leading to the identification of 20 promising plasma and 14 CSF metabolites. These metabolites differentiated the test set with an AUC of 0.8 (plasma) and 0.9 (CSF). Characteristics of the metabolites indicate perturbations in the glycerophospholipid, sphingolipid, and amino acid metabolism in PD, which underscores the high power of metabolomic approaches. Further studies will enable to develop a potential metabolite-based biomarker panel specific for PD

Strategy to achieve biomarker-driven immunosuppression after solid organ transplantation by an academic-industry partnership within the European BIO-DrIM consortium

Solid organ transplantation has emerged as the “gold standard” therapy for end-stage organ failure as it improves both quality of life and survival. Despite the progress in short-term graft survival, that is closely associated with the impressive reduction of acute rejections within the first year, long-term graft and patient survival remain almost un-changed and unsatisfactory. Incomplete control of chronic allograft injury but particularly the adverse effects of long-term immunosuppression, such as graft toxicity, diabetes, cardiovascular events, infections, and tumours continue to challenge the long-term success. In general, immunosuppression is applied as one-size-fits-all strategy. This can result in over- and under-immunosuppression of patients with low and high alloresponsiveness, respectively. Trial- and -error strategies to minimize or even completely wean of immunosuppression have a high failure rate. Consequently, there is an unmet medical need to develop biomarkers allowing objective risk stratification of transplant patients. To achieve this goal, we engaged in an academic-industrial partnership. The central focus of the European-wide BIO-DrIM consortium (BIOmarker-Driven IMmmunosuppression) is the implementation of biomarker-guided strategies for personalizing immunosuppression to improve the long-term outcome and to decrease the adverse effects and costs of chronic immunosuppression in solid organ transplant patients. The concept includes four innovative investigator-driven clinical trials designed by the consortium

Familial Resemblance for Loneliness

Social isolation and loneliness in humans have been associated with physical and psychological morbidity, as well as mortality. This study aimed to assess the etiology of individual differences in feelings of loneliness. The genetic architecture of loneliness was explored in an extended twin-family design including 8,683 twins, siblings and parents from 3,911 families. In addition, 917 spouses of twins participated. The presence of assortative mating, genetic non-additivity, vertical cultural transmission, genotype–environment (GE) correlation and interaction was modeled. GE interaction was considered for several demographic characteristics. Results showed non-random mating for loneliness. We confirmed that loneliness is moderately heritable, with a significant contribution of non-additive genetic variation. There were no effects of vertical cultural transmission. With respect to demographic characteristics, results indicated that marriage, having offspring, more years of education, and a higher number of siblings are associated with lower levels of loneliness. Interestingly, these effects tended to be stronger for men than women. There was little evidence of changes in genetic architecture as a function of these characteristics. We conclude that the genetic architecture of loneliness points to non-additive genetic influences, suggesting it may be a trait that was not neutral to selection in our evolutionary past. Sociodemographic factors that influence the prevalence of loneliness do not affect its genetic architecture

Long- and short-term outcomes in renal allografts with deceased donors: A large recipient and donor genome-wide association study.

Improvements in immunosuppression have modified short-term survival of deceased-donor allografts, but not their rate of long-term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short- and long-term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large-scale genome-wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant-pairs with replication in 5866 complete pairs. We studied deceased-donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long- or short-term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application

Exercise Participation in Adolescents and Their Parents: Evidence for Genetic and Generation Specific Environmental Effects

Individual differences in adolescent exercise behavior are to a large extent explained by shared environmental factors. The aim of this study was to explore to what extent this shared environment represents effects of cultural transmission of parents to their offspring, generation specific environmental effects or assortative mating. Survey data on leisure-time exercise behavior were available from 3,525 adolescent twins and their siblings (13-18 years) and 3,138 parents from 1,736 families registered at the Netherlands Twin Registry. Data were also available from 5,471 adult twins, their siblings and spouses similar in age to the parents. Exercise participation (No/Yes, using a cut-off criterion of 4 metabolic equivalents and 60 min weekly) was based on questions on type, frequency and duration of exercise. A model to analyze dichotomous data from twins, siblings and parents including differences in variance decomposition across sex and generation was developed. Data from adult twins and their spouses were used to investigate the causes of assortative mating (correlation between spouses = 0.41, due to phenotypic assortment). The heritability of exercise in the adult generation was estimated at 42%. The shared environment for exercise behavior in adolescents mainly represents generation specific shared environmental influences that seem somewhat more important in explaining familial clustering in girls than in boys (52 versus 41%). A small effect of vertical cultural transmission was found for boys only (3%). The remaining familial clustering for exercise behavior was explained by additive genetic factors (42% in boys and 36% in girls). Future studies on adolescent exercise behavior should focus on identification of the generation specific environmental factors. © 2010 Springer Science+Business Media, LLC

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]

Evidence synthesis to inform model-based cost-effectiveness evaluations of diagnostic tests: a methodological systematic review of health technology assessments

Background: Evaluations of diagnostic tests are challenging because of the indirect nature of their impact on patient outcomes. Model-based health economic evaluations of tests allow different types of evidence from various sources to be incorporated and enable cost-effectiveness estimates to be made beyond the duration of available study data. To parameterize a health-economic model fully, all the ways a test impacts on patient health must be quantified, including but not limited to diagnostic test accuracy. Methods: We assessed all UK NIHR HTA reports published May 2009-July 2015. Reports were included if they evaluated a diagnostic test, included a model-based health economic evaluation and included a systematic review and meta-analysis of test accuracy. From each eligible report we extracted information on the following topics: 1) what evidence aside from test accuracy was searched for and synthesised, 2) which methods were used to synthesise test accuracy evidence and how did the results inform the economic model, 3) how/whether threshold effects were explored, 4) how the potential dependency between multiple tests in a pathway was accounted for, and 5) for evaluations of tests targeted at the primary care setting, how evidence from differing healthcare settings was incorporated. Results: The bivariate or HSROC model was implemented in 20/22 reports that met all inclusion criteria. Test accuracy data for health economic modelling was obtained from meta-analyses completely in four reports, partially in fourteen reports and not at all in four reports. Only 2/7 reports that used a quantitative test gave clear threshold recommendations. All 22 reports explored the effect of uncertainty in accuracy parameters but most of those that used multiple tests did not allow for dependence between test results. 7/22 tests were potentially suitable for primary care but the majority found limited evidence on test accuracy in primary care settings. Conclusions: The uptake of appropriate meta-analysis methods for synthesising evidence on diagnostic test accuracy in UK NIHR HTAs has improved in recent years. Future research should focus on other evidence requirements for cost-effectiveness assessment, threshold effects for quantitative tests and the impact of multiple diagnostic tests

Erratum to: Methods for evaluating medical tests and biomarkers

[This corrects the article DOI: 10.1186/s41512-016-0001-y.]