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1.
JAMA Neurol ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749724

RESUMO

Importance: Incidental findings (IFs) are unexpected abnormalities discovered during imaging and can range from normal anatomic variants to findings requiring urgent medical intervention. In the case of brain magnetic resonance imaging (MRI), reliable data about the prevalence and significance of IFs in the general population are limited, making it difficult to anticipate, communicate, and manage these findings. Objectives: To determine the overall prevalence of IFs in brain MRI in the nonclinical pediatric population as well as the rates of specific findings and findings for which clinical referral is recommended. Design, Setting, and Participants: This cohort study was based on the April 2019 release of baseline data from 11 810 children aged 9 to 10 years who were enrolled and completed baseline neuroimaging in the Adolescent Brain Cognitive Development (ABCD) study, the largest US population-based longitudinal observational study of brain development and child health, between September 1, 2016, and November 15, 2018. Participants were enrolled at 21 sites across the US designed to mirror the demographic characteristics of the US population. Baseline structural MRIs were centrally reviewed for IFs by board-certified neuroradiologists and findings were described and categorized (category 1, no abnormal findings; 2, no referral recommended; 3; consider referral; and 4, consider immediate referral). Children were enrolled through a broad school-based recruitment process in which all children of eligible age at selected schools were invited to participate. Exclusion criteria were severe sensory, intellectual, medical, or neurologic disorders that would preclude or interfere with study participation. During the enrollment process, demographic data were monitored to ensure that the study met targets for sex, socioeconomic, ethnic, and racial diversity. Data were analyzed from March 15, 2018, to November 20, 2020. Main Outcomes and Measures: Percentage of children with IFs in each category and prevalence of specific IFs. Results: A total of 11 679 children (52.1% boys, mean [SD] age, 9.9 [0.62] years) had interpretable baseline structural MRI results. Of these, 2464 participants (21.1%) had IFs, including 2013 children (17.2%) assigned to category 2, 431 (3.7%) assigned to category 3, and 20 (0.2%) assigned to category 4. Overall rates of IFs did not differ significantly between singleton and twin gestations or between monozygotic and dizygotic twins, but heritability analysis showed heritability for the presence or absence of IFs (h2 = 0.260; 95% CI, 0.135-0.387). Conclusions and Relevance: Incidental findings in brain MRI and findings with potential clinical significance are both common in the general pediatric population. By assessing IFs and concurrent developmental and health measures and following these findings over the longitudinal study course, the ABCD study has the potential to determine the significance of many common IFs.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33723363

RESUMO

BACKGROUND: Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death. METHODS: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests. RESULTS: Median age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p < 10-15). CONCLUSIONS: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.

3.
Neurosci Lett ; 750: 135753, 2021 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-33610673

RESUMO

This article provides a succinct overview of sex differences in epilepsy and putative molecular mechanisms underlying sex differences in seizure susceptibility in chemical, genetic, and acquired epileptogenesis. The susceptibility to excitability episodes and occurrence of epileptic seizures are generally higher in men than women. The precise molecular mechanisms remain unclear, but differences in regional morphology and neural circuits in men and women may explain differential vulnerability to seizures and epileptogenic cascades. Changes in seizure sensitivity can be attributed to steroid hormones, including fluctuations in neurosteroids as well as neuroplasticity in their receptor signaling systems. Other potential neurobiological bases for sex differences in epilepsies include differences in brain development, neurogenesis, neuronal chloride homeostasis, and neurotrophic and glial responses. In catamenial epilepsy, a gender-specific neuroendocrine condition, epileptic seizures are most often clustered around a specific menstrual period in adult women. A deeper understanding of the molecular and neural network basis of sex differences in seizures and response to antiepileptic drugs is highly warranted for designing effective, sex-specific therapies for epilepsy, epileptogenesis, and seizure disorders.

4.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623038

RESUMO

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.


Assuntos
Grupos Étnicos/genética , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Autorrelato
5.
Artigo em Inglês | MEDLINE | ID: mdl-33547597

RESUMO

This chapter describes the experimental evidence of stress modulation of epileptic seizures and the potential role of corticosteroids and neurosteroids in regulating stress-linked seizure vulnerability. Epilepsy is a chronic neurological disorder that is characterized by repeated seizures. There are many potential causes for epilepsy, including genetic predispositions, infections, brain injury, and neurotoxicity. Stress is a known precipitating factor for seizures in individuals suffering from epilepsy. Severe acute stress and persistent exposure to stress may increase susceptibility to seizures, thereby resulting in a higher frequency of seizures. This occurs through the stress-mediated release of cortisol, which has both excitatory and proconvulsant properties. Stress also causes the release of endogenous neurosteroids from central and adrenal sources. Neurosteroids such as allopregnanolone and THDOC, which are allosteric modulators of GABA-A receptors, are powerful anticonvulsants and neuroprotectants. Acute stress increases the release of neurosteroids, while chronic stress is associated with severe neurosteroid depletion and reduced inhibition in the brain. This diminished inhibition occurs largely as a result of neurosteroid deficiencies. Thus, exogenous administration of neurosteroids (neurosteroid replacement therapy) may offer neuroprotection in epilepsy. Synthetic neurosteroid could offer a rational approach to control neurosteroid-sensitive, stress-related epileptic seizures.

6.
Contemp Clin Trials ; 103: 106330, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33631357

RESUMO

BACKGROUND AND AIMS: Retrospective studies have shown that angiotensin-converting-enzyme (ACE) inhibitors are associated with a reduced risk of complications and mortality in persons with novel coronavirus disease 2019 (COVID-19). Thus, we aimed to examine the efficacy of ramipril, an ACE-inhibitor, in preventing ICU admission, mechanical ventilation and/or mortality while also minimizing the risk of transmission and use of personal protective equipment (PPE). METHODS: RAMIC is a multicenter, randomized, double-blind, allocation-concealed, placebo-controlled trial comparing the efficacy of treatment with ramipril 2.5 mg orally daily compared to placebo for 14 days. The study population includes adult patients with COVID-19 who were admitted to a hospital or assessed in an emergency department or ambulatory clinic. Key exclusion criteria include ICU admission or need for mechanical ventilation at screening, use of an ACE inhibitor or angiotensin-receptor-II blocker within 7 days, glomerular filtration rate < 40 mL/min or a systolic blood pressure (BP) < 100 mmHg or diastolic BP < 65 mmHg. Patients are randomized 2:1 to receive ramipril (2.5 mg) or placebo daily. Informed consent and study visits occur virtually to minimize the risk of SARS-CoV-2 transmission and preserve PPE. The primary composite endpoint of ICU admission, invasive mechanical ventilation and death are adjudicated virtually. CONCLUSIONS: RAMIC is designed to assess the efficacy of treatment with ramipril for 14 days to decrease ICU admission, mechanical ventilator use and mortality in patients with COVID-19 and leverages virtual study visits and endpoint adjudication to mitigate risk of infection and to preserve PPE (ClinicalTrials.gov, NCT04366050).

7.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

8.
JAMA Psychiatry ; 78(4): 407-415, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33377940

RESUMO

Importance: Maturation of white matter fiber systems subserves cognitive, behavioral, emotional, and motor development during adolescence. Hazardous drinking during this active neurodevelopmental period may alter the trajectory of white matter microstructural development, potentially increasing risk for developing alcohol-related dysfunction and alcohol use disorder in adulthood. Objective: To identify disrupted adolescent microstructural brain development linked to drinking onset and to assess whether the disruption is more pronounced in younger rather than older adolescents. Design, Setting, and Participants: This case-control study, conducted from January 13, 2013, to January 15, 2019, consisted of an analysis of 451 participants from the National Consortium on Alcohol and Neurodevelopment in Adolescence cohort. Participants were aged 12 to 21 years at baseline and had at least 2 usable magnetic resonance diffusion tensor imaging (DTI) scans and up to 5 examination visits spanning 4 years. Participants with a youth-adjusted Cahalan score of 0 were labeled as no-to-low drinkers; those with a score of greater than 1 for at least 2 consecutive visits were labeled as heavy drinkers. Exploratory analysis was conducted between no-to-low and heavy drinkers. A between-group analysis was conducted between age- and sex-matched youths, and a within-participant analysis was performed before and after drinking. Exposures: Self-reported alcohol consumption in the past year summarized by categorical drinking levels. Main Outcomes and Measures: Diffusion tensor imaging measurement of fractional anisotropy (FA) in the whole brain and fiber systems quantifying the developmental change of each participant as a slope. Results: Analysis of whole-brain FA of 451 adolescents included 291 (64.5%) no-to-low drinkers and 160 (35.5%) heavy drinkers who indicated the potential for a deleterious association of alcohol with microstructural development. Among the no-to-low drinkers, 142 (48.4%) were boys with mean (SD) age of 16.5 (2.2) years and 149 (51.2%) were girls with mean (SD) age of 16.5 (2.1) years and 192 (66.0%) were White participants. Among the heavy drinkers, 86 (53.8%) were boys with mean (SD) age of 20.1 (1.5) years and 74 (46.3%) were girls with mean (SD) age of 20.5 (2.0) years and 142 (88.8%) were White participants. A group analysis revealed FA reduction in heavy-drinking youth compared with age- and sex-matched controls (t154 = -2.7, P = .008). The slope of this reduction correlated with log of days of drinking since the baseline visit (r156 = -0.21, 2-tailed P = .008). A within-participant analysis contrasting developmental trajectories of youths before and after they initiated heavy drinking supported the prediction that drinking onset was associated with and potentially preceded disrupted white matter integrity. Age-alcohol interactions (t152 = 3.0, P = .004) observed for the FA slopes indicated that the alcohol-associated disruption was greater in younger than older adolescents and was most pronounced in the genu and body of the corpus callosum, regions known to continue developing throughout adolescence. Conclusions and Relevance: This case-control study of adolescents found a deleterious association of alcohol use with white matter microstructural integrity. These findings support the concept of heightened vulnerability to environmental agents, including alcohol, associated with attenuated development of major white matter tracts in early adolescence.

9.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.

11.
PLoS Genet ; 16(11): e1009163, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33227023

RESUMO

Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

12.
BMC Public Health ; 20(1): 1783, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33238925

RESUMO

BACKGROUND: Screen media is among the most common recreational activities engaged in by children. The displacement hypothesis predicts that increased time spent on screen media activity (SMA) may be at the expense of engagement with other recreational activities, such as sport, music, and art. This study examined associations between non-educational SMA and recreational activity endorsement in 9-10-year-olds, when accounting for other individual (i.e., cognition, psychopathology), interpersonal (i.e., social environment), and sociodemographic characteristics. METHODS: Participants were 9254 youth from the Adolescent Brain Cognitive Development Study®. Latent factors reflecting SMA, cognition, psychopathology, and social environment were entered as independent variables into logistic mixed models. Sociodemographic covariates included age, sex, race/ethnicity, education, marital status, and household income. Outcome variables included any recreational activity endorsement (of 19 assessed), and specific sport (swimming, soccer, baseball) and hobby (music, art) endorsements. RESULTS: In unadjusted groupwise comparisons, youth who spent more time engaging with SMA were less likely to engage with other recreational activities (ps < .001). However, when variance in cognition, psychopathology, social environment, and sociodemographic covariates were accounted for, most forms of SMA were no longer significantly associated with recreational activity engagement (p > .05). Some marginal effects were observed: for every one SD increase in time spent on games and movies over more social forms of media, youth were at lower odds of engaging in recreational activities (adjusted odds ratio = 0·83, 95% CI 0·76-0·89). Likewise, greater general SMA was associated with lower odds of endorsing group-based sports, including soccer (0·93, 0·88-0·98) and baseball (0·92, 0·86-0·98). Model fit comparisons indicated that sociodemographic characteristics, particularly socio-economic status, explained more variance in rates of recreational activity engagement than SMA and other latent factors. Notably, youth from higher socio-economic families were up to 5·63 (3·83-8·29) times more likely to engage in recreational activities than youth from lower socio-economic backgrounds. CONCLUSIONS: Results did not suggest that SMA largely displaces engagement in other recreational activities among 9-10-year-olds. Instead, socio-economic factors greatly contribute to rates of engagement. These findings are important considering recent shifts in time spent on SMA in childhood.

13.
Front Hum Neurosci ; 14: 578822, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192411

RESUMO

While low socioeconomic status (SES) introduces risk for developmental outcomes among children, there are an array of proximal processes that determine the ecologies and thus the lived experiences of children. This study examined interrelations between 22 proximal measures in the economic, psychosocial, physiological, and perinatal ecologies of children, in association with brain structure and cognitive performance in a diverse sample of 8,158 9-10-year-old children from the Adolescent Brain Cognitive Development (ABCD) study. SES was measured by the income-to-needs ratio (INR), a measure used by federal poverty guidelines. Within the ABCD study, in what is one of the largest and most diverse cohorts of children studied in the United States, we replicate associations of low SES with lower total cortical surface area and worse cognitive performance. Associations between low SES (<200% INR) and measures of development showed the steepest increases with INR, with apparent increases still visible beyond the level of economic disadvantage in the range of 200-400% INR. Notably, we found three latent factors encompassing positive ecologies for children across the areas of economic, psychosocial, physiological, and perinatal well-being in association with better cognitive performance and the higher total cortical surface area beyond the effects of SES. Specifically, latent factors encompassing youth perceived social support and perinatal well-being were positive predictors of developmental measures for all children, regardless of SES. Further, we found a general latent factor that explained relationships between 20 of the proximal measures and encompassed a joint ecology of higher social and economic resources relative to low adversity across psychosocial, physiological, and perinatal domains. The association between the resource-to-adversity latent factor and cognitive performance was moderated by SES, such that for children in higher SES households, cognitive performance progressively increased with these latent factor scores, while for lower SES, cognitive performance increased only among children with the highest latent factor scores. Our findings suggest that both positive ecologies of increased access to resources and lower adversity are mutually critical for promoting better cognitive development in children from low SES households. Our findings inform future studies aiming to examine positive factors that influence healthier development in children.

14.
Nat Hum Behav ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168953

RESUMO

Although the genetic influence on voter turnout is substantial (typically 40-50%), the underlying mechanisms remain unclear. Across the social sciences, research suggests that 'resources for politics' (as indexed notably by educational attainment and intelligence test performance) constitute a central cluster of factors that predict electoral participation. Educational attainment and intelligence test performance are heritable. This suggests that the genotypes that enhance these phenotypes could positively predict turnout. To test this, we conduct a genome-wide complex trait analysis of individual-level turnout. We use two samples from the Danish iPSYCH case-cohort study, including a nationally representative sample as well as a sample of individuals who are particularly vulnerable to political alienation due to psychiatric conditions (n = 13,884 and n = 33,062, respectively). Using validated individual-level turnout data from the administrative records at the polling station, genetic correlations and Mendelian randomization, we show that there is a substantial genetic overlap between voter turnout and both educational attainment and intelligence test performance.

15.
J AOAC Int ; 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33175165

RESUMO

BACKGROUND: One Broth One Plate for Salmonella (OBOP Salmonella) is a rapid and simple method for detection of Salmonella spp. in food and environmental samples using traditional culture methodology. The method utilizes single-step enrichment followed by plating to a selective/differential, chromogenic agar. OBJECTIVE: The purpose of the validation study was to measure the effectiveness of the OBOP Salmonella method in comparison to reference culture procedures. METHODS: Performance of the OBOP Salmonella method was compared to that of the U.S. Food and Drug Administration Bacteriological Analytical Manual Chapter 5 reference method for queso fresco, smoked salmon, cantaloupe, chocolate, black pepper, chili powder, dry pet food, and sponge samples from a stainless steel surface, or to that of the U.S. Department of Agriculture Microbiology Laboratory Guidebook Chapter 4.10 method for raw ground turkey, chicken carcass rinse, and pasteurized liquid egg. Inclusivity/exclusivity, robustness, and stability/lot-to-lot consistency testing was also performed. RESULTS: In the matrix study, there were no statistically significant differences in performance between the OBOP Salmonella and reference methods, as determined by probability of detection analysis (P < 0.05), for any of the matrixes examined. All 104 Salmonella spp. strains produced positive results in inclusivity testing, and all 33 non-salmonellae exclusivity strains tested negative with the OBOP Salmonella method. CONCLUSIONS: Results of the validation study show that the OBOP Salmonella method is a reliable procedure for detection of Salmonella spp. in select matrixes. The method is simple to perform, requires no specialized equipment, and produces results in as little as 37 h.

16.
Cereb Cortex ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33145600

RESUMO

Despite its central role in revealing the neurobiological mechanisms of behavior, neuroimaging research faces the challenge of producing reliable biomarkers for cognitive processes and clinical outcomes. Statistically significant brain regions, identified by mass univariate statistical models commonly used in neuroimaging studies, explain minimal phenotypic variation, limiting the translational utility of neuroimaging phenotypes. This is potentially due to the observation that behavioral traits are influenced by variations in neuroimaging phenotypes that are globally distributed across the cortex and are therefore not captured by thresholded, statistical parametric maps commonly reported in neuroimaging studies. Here, we developed a novel multivariate prediction method, the Bayesian polyvertex score, that turns a unthresholded statistical parametric map into a summary score that aggregates the many but small effects across the cortex for behavioral prediction. By explicitly assuming a globally distributed effect size pattern and operating on the mass univariate summary statistics, it was able to achieve higher out-of-sample variance explained than mass univariate and popular multivariate methods while still preserving the interpretability of a generative model. Our findings suggest that similar to the polygenicity observed in the field of genetics, the neural basis of complex behaviors may rest in the global patterning of effect size variation of neuroimaging phenotypes, rather than in localized, candidate brain regions and networks.

17.
Proc Natl Acad Sci U S A ; 117(43): 26977-26984, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33046629

RESUMO

The prevalence of obesity in children and adolescents worldwide has quadrupled since 1975 and is a key predictor of obesity later in life. Previous work has consistently observed relationships between macroscale measures of reward-related brain regions (e.g., the nucleus accumbens [NAcc]) and unhealthy eating behaviors and outcomes; however, the mechanisms underlying these associations remain unclear. Recent work has highlighted a potential role of neuroinflammation in the NAcc in animal models of diet-induced obesity. Here, we leverage a diffusion MRI technique, restriction spectrum imaging, to probe the microstructure (cellular density) of subcortical brain regions. More specifically, we test the hypothesis that the cell density of reward-related regions is associated with obesity-related metrics and early weight gain. In a large cohort of nine- and ten-year-olds enrolled in the Adolescent Brain Cognitive Development (ABCD) study, we demonstrate that cellular density in the NAcc is related to individual differences in waist circumference at baseline and is predictive of increases in waist circumference after 1 y. These findings suggest a neurobiological mechanism for pediatric obesity consistent with rodent work showing that high saturated fat diets increase gliosis and neuroinflammation in reward-related brain regions, which in turn lead to further unhealthy eating and obesity.

18.
Bioinformatics ; 2020 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-33070187

RESUMO

MOTIVATION: Network diffusion and label propagation are fundamental tools in computational biology, with applications like gene-disease association, protein function prediction and module discovery. More recently, several publications have introduced a permutation analysis after the propagation process, due to concerns that network topology can bias diffusion scores. This opens the question of the statistical properties and the presence of bias of such diffusion processes in each of its applications. In this work, we characterised some common null models behind the permutation analysis and the statistical properties of the diffusion scores. We benchmarked seven diffusion scores on three case studies: synthetic signals on a yeast interactome, simulated differential gene expression on a protein-protein interaction network and prospective gene set prediction on another interaction network. For clarity, all the datasets were based on binary labels, but we also present theoretical results for quantitative labels. RESULTS: Diffusion scores starting from binary labels were affected by the label codification, and exhibited a problem-dependent topological bias that could be removed by the statistical normalisation. Parametric and non-parametric normalisation addressed both points by being codification-independent and by equalising the bias. We identified and quantified two sources of bias -mean value and variance- that yielded performance differences when normalising the scores. We provided closed formulae for both and showed how the null covariance is related to the spectral properties of the graph. Despite none of the proposed scores systematically outperformed the others, normalisation was preferred when the sought positive labels were not aligned with the bias. We conclude that the decision on bias removal should be problem and data-driven, i.e. based on a quantitative analysis of the bias and its relation to the positive entities. AVAILABILITY: The code is publicly available at https://github.com/b2slab/diffuBench. CONTACT: sergi.picart@upc.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

19.
Sci Rep ; 10(1): 17248, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057110

RESUMO

The muscular dystrophy X-linked mouse (mdx) is the most commonly used preclinical model for Duchenne muscular dystrophy. Although disease progression in the mouse does not perfectly model the human disease, it shares many pathological features. Early characterizations of the model reported severe pathology through early adulthood followed by disease stabilization. As a result, research in the mdx mouse has largely focused on early adulthood. The overarching goal of this study is to improve the understanding of the mdx mouse model by tracking pathological features of the disease throughout life. We performed a thorough characterization of myofiber pathology in mdx mice from 2 weeks to 2 years of age. We report that individual mdx muscle fibers undergo progressive hypertrophy that continues through the lifespan. Despite massive hypertrophy on the myofiber level, we report no hypertrophy on the muscle level. These seemingly contradictory findings are explained by previously underappreciated myofiber loss in mdx mice. We conclude that due to myofiber loss, in combination with the progressive nature of other pathological features, aged mdx muscle tissue provides reliable benchmarks for disease progression that may be valuable in testing the efficacy of therapeutics for Duchenne muscular dystrophy.

20.
Nat Commun ; 11(1): 4700, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929091

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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