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1.
Parkinsonism Relat Disord ; 69: 48-54, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31677455

RESUMO

INTRODUCTION: Females have a reduced risk of Parkinson's disease (PD). However, it is unclear if sex is a prognostic factor. We aimed to examine differences in presentation, physician- and patient-reported PD outcomes, and progression by sex in a large clinical cohort. METHODS: This study was a secondary analysis of a cohort of PD patients seen at a tertiary care center. Sociodemographic and clinical characteristics, treatment, care timing, and outcomes were examined by sex. Sex differences in progression of impairment, disability, and health-related quality of life (HRQoL) were tested with five-year piecewise linear mixed-effects models. A mediation analysis assessed drivers of sex differences. RESULTS: The study included 914 males and 549 females. Females had significantly less social support, more psychological distress, and worse self-reported (but not physician-reported) disability and HRQoL at initial PD care visits, compared to males. Addressing anxiety symptoms may attenuate this difference. PD progression sex differences were minimal. CONCLUSION: PD progression does not differ by sex, yet patient-reported measures of disease severity are worse in females than males. To attenuate this sex difference in disease experience, psychological distress screening and management, particularly targeting females, should be implemented as part of PD clinical care.

2.
Neuroimage Clin ; 23: 101884, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31200151

RESUMO

White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.

3.
Stroke ; 50(7): 1734-1741, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31177973

RESUMO

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

4.
Neurol Genet ; 3(5): e180, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28852707

RESUMO

OBJECTIVE: To describe the design and rationale for the genetic analysis of acute and chronic cerebrovascular neuroimaging phenotypes detected on clinical MRI in patients with acute ischemic stroke (AIS) within the scope of the MRI-GENetics Interface Exploration (MRI-GENIE) study. METHODS: MRI-GENIE capitalizes on the existing infrastructure of the Stroke Genetics Network (SiGN). In total, 12 international SiGN sites contributed MRIs of 3,301 patients with AIS. Detailed clinical phenotyping with the web-based Causative Classification of Stroke (CCS) system and genome-wide genotyping data were available for all participants. Neuroimaging analyses include the manual and automated assessments of established MRI markers. A high-throughput MRI analysis pipeline for the automated assessment of cerebrovascular lesions on clinical scans will be developed in a subset of scans for both acute and chronic lesions, validated against gold standard, and applied to all available scans. The extracted neuroimaging phenotypes will improve characterization of acute and chronic cerebrovascular lesions in ischemic stroke, including CCS subtypes, and their effect on functional outcomes after stroke. Moreover, genetic testing will uncover variants associated with acute and chronic MRI manifestations of cerebrovascular disease. CONCLUSIONS: The MRI-GENIE study aims to develop, validate, and distribute the MRI analysis platform for scans acquired as part of clinical care for patients with AIS, which will lead to (1) novel genetic discoveries in ischemic stroke, (2) strategies for personalized stroke risk assessment, and (3) personalized stroke outcome assessment.

5.
Mol Genet Metab Rep ; 10: 84-91, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28154797

RESUMO

CONTEXT: Sulfate is critical in the biotransformation of multiple compounds via sulfation. These compounds include neurotransmitters, proteoglycans, xenobiotics, and hormones such as dehydroepiandrosterone (DHEA). Sulfation reactions are thought to be rate-limited by endogenous sulfate concentrations. The gene, SLC13A1, encodes the sodium-sulfate cotransporter NaS1, responsible for sulfate (re)absorption in the intestines and kidneys. We previously reported two rare, non-linked, nonsense variants in SLC13A1 (R12X and W48X) associated with hyposulfatemia (P = 9 × 10- 20). OBJECTIVE: To examine the effect of serum sulfate concentration and sulfate-lowering genotype on DHEA homeostasis. DESIGN: Retrospective cohort study. SETTING: Academic research. PATIENTS: Participants of the Amish Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and the Amish Hereditary and Phenotype Intervention (HAPI) Study. MAIN OUTCOME MEASURES: DHEA, DHEA-S, and DHEA-S/DHEA ratio. RESULTS: Increased serum sulfate was associated with decreased DHEA-S (P = 0.03) and DHEA-S/DHEA ratio (P = 0.06) in males but not females. Female SLC13A1 nonsense variant carriers, who had lower serum sulfate (P = 9 × 10- 13 ), exhibited 14% lower DHEA levels (P = 0.01) and 7% higher DHEA-S/DHEA ratios compared to female non-carriers (P = 0.002). Consistent with this finding, female SLC13A1 nonsense variant carriers also had lower total testosterone levels compared to non-carrier females (P = 0.03). CONCLUSIONS: Our results demonstrate an inverse relationship between serum sulfate, and DHEA-S and DHEA-S/DHEA ratio in men, while also suggesting that the sulfate-lowering variants, SLC13A1 R12X and W48X, decrease DHEA and testosterone levels, and increase DHEA-S/DHEA ratio in women. While paradoxical, these results illustrate the complexity of the mechanisms involved in DHEA homeostasis and warrant additional studies to better understand sulfate's role in hormone physiology.

6.
Ann Neurol ; 81(3): 383-394, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27997041

RESUMO

OBJECTIVE: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. METHODS: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. RESULTS: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10-1.22]; p = 3.2 × 10-9 ). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05-1.16]; p = 5.3 × 10-5 ; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84-1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7 ) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6 ). INTERPRETATION: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383-394.


Assuntos
Doenças de Pequenos Vasos Cerebrais/genética , Cromossomos Humanos Par 16/genética , Estudo de Associação Genômica Ampla , Acidente Vascular Cerebral/genética , Dedos de Zinco/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Loci Gênicos , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral Lacunar/genética
7.
J Nutrigenet Nutrigenomics ; 9(5-6): 254-264, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28002826

RESUMO

BACKGROUND/AIMS: Alpha-carotene is a provitamin A carotenoid present in fruits and vegetables. Higher serum concentrations of α-carotene have been associated with lower risk of cancer and all-cause mortality. Previous studies have suggested that genetic variants influence serum concentrations of provitamin A carotenoids, but to date no variants have been robustly associated with serum α-carotene concentrations. The aim of this study was to identify genetic associations with serum α-carotene concentrations using the genome-wide association study (GWAS) approach. METHODS: A GWAS of serum α-carotene concentrations was conducted in 433 Old Order Amish adults who had consumed a 6-day controlled diet. Linear regression models adjusting for age, gender, and family structure were utilized to evaluate associations between genetic variants and serum α-carotene concentrations. RESULTS: Genome-wide significant associations with α-carotene concentrations were observed for loci on chromosome 1q41 between the genes CAPN2 and CAPN8 (rs12137025, p = 3.55 × 10-8), chromosome 2p21 in PRKCE (rs2594495, p = 1.01 × 10-8), and chromosome 4q34 (rs17830069, p = 2.89 × 10-8). CONCLUSIONS: We identified 3 novel loci associated with serum α-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum α-carotene concentrations and may suggest a relationship with the development and progression of cancers.


Assuntos
Calpaína/genética , Carotenoides/sangue , Cromossomos Humanos Par 1 , Loci Gênicos , Adulto , Amish/genética , Dieta , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Diabetes ; 65(10): 2824-5, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27659224
9.
Am J Health Promot ; 30(5): 346-56, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27404643

RESUMO

PURPOSE: To determine whether an experiential nutrition education intervention focusing on spices and herbs ("Spice MyPlate") is feasible and improves diet quality and healthy eating attitudes among an urban and predominantly African-American sample of adolescents more than standard nutrition education alone. DESIGN: A nonrandomized controlled trial compared standard nutrition education in U.S. Department of Agriculture MyPlate guidelines (control group) with standard nutrition education plus adjuvant Spice MyPlate curriculum (intervention group). Data were collected at baseline and after 3, 6, and 10 weeks. SETTING: Study setting was two public high schools in Baltimore, Maryland. SUBJECTS: A total of 110 students in grades 9 to 12 participated. INTERVENTION: The 6-week school-based intervention conducted during health class focused on cooking using spices and herbs to eat healthier diets according to MyPlate. MEASURES: Dietary intake reported on 3-day food records and healthy eating attitudes questionnaires was analyzed. ANALYSIS: Differences in diet quality and healthy eating attitudes between study groups were estimated by t-tests, Wilcoxon-Mann-Whitney tests, and covariate-adjusted regression models. RESULTS: Spice MyPlate was feasible and there were modest but significant improvements (p ≤ .05) in the Spice MyPlate group compared with control in whole grains (31.2 g/wk) and protein foods (13.2 ounces per week) intake, and attitudes toward eating vegetables, whole grains, lean protein, and low-fat dairy. CONCLUSIONS: Although randomized trials are needed, experiential nutrition education focusing on spices and herbs may help urban and predominantly African-American adolescent populations eat healthier diets.


Assuntos
Atitude Frente a Saúde , Dieta/psicologia , Ciências da Nutrição/educação , Serviços de Saúde Escolar , Especiarias , Estudantes/psicologia , Adolescente , Culinária/métodos , Dieta/estatística & dados numéricos , Feminino , Humanos , Masculino
10.
Nutrients ; 8(2): 82, 2016 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-26861389

RESUMO

Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS) approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10(-9)). Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841) in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.


Assuntos
Antioxidantes/metabolismo , Carotenoides/sangue , Genótipo , Histona-Lisina N-Metiltransferase/genética , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Adulto , Amish , Dieta , Feminino , Estudo de Associação Genômica Ampla , Humanos , Íntrons , Licopeno , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/sangue
12.
Am J Epidemiol ; 182(9): 747-9, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26476284

RESUMO

Data visualization is an important tool that epidemiologists use to communicate with others in the field. The American Journal of Epidemiology recently acknowledged the importance of data visualization by inaugurating an award for the "Figure of the Year." Yet, creating figures that adhere to the standards of the Journal is a challenge. The purpose of the present article was to provide helpful hints for creating figures in SAS/GRAPH that meet the requirements of the Journal. It stresses 3 techniques: properly sizing figures overall, sizing text within a figure, and creating acceptable file formats. This information will prove useful to authors who create data-driven figures intended to be published in the Journal.


Assuntos
Epidemiologia , Publicações Periódicas como Assunto , Editoração/normas , Software , Estatística como Assunto , Humanos
13.
Nat Genet ; 47(11): 1294-1303, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26414677

RESUMO

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.


Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Reparo do DNA , Predisposição Genética para Doença/genética , Hipotálamo/metabolismo , Transdução de Sinais/genética , Adulto , Fatores Etários , Envelhecimento/genética , Feminino , Redes Reguladoras de Genes/genética , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Genômica/métodos , Genótipo , Humanos , Menopausa/genética , Pessoa de Meia-Idade , Modelos Genéticos , Fenótipo , Reprodução/genética
14.
Stroke ; 46(6): 1690-2, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25944320

RESUMO

BACKGROUND AND PURPOSE: Body mass index has been associated with ischemic stroke in older populations, but its association with stroke in younger populations is not known. In light of the current obesity epidemic in the United States, the potential impact of obesity on stroke risk in young adults deserves attention. METHODS: A population-based case-control study design with 1201 cases and 1154 controls was used to investigate the relationship of obesity and young onset ischemic stroke. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between body mass index and ischemic stroke with and without adjustment for comorbid conditions associated with stroke. RESULTS: In analyses adjusted for age, sex, and ethnicity, obesity (body mass index >30 kg/m(2)) was associated with an increased stroke risk (odds ratio, 1.57; 95% confidence interval, 1.28-1.94) although this increased risk was highly attenuated and not statistically significant after adjustment for smoking, hypertension, and diabetes mellitus. CONCLUSIONS: These results indicate that obesity is a risk factor for young onset ischemic stroke and suggest that this association may be partially mediated through hypertension, diabetes mellitus, or other variables associated with these conditions.


Assuntos
Índice de Massa Corporal , Isquemia Encefálica/epidemiologia , Obesidade/epidemiologia , Acidente Vascular Cerebral/epidemiologia , Adolescente , Adulto , Idade de Início , Isquemia Encefálica/etiologia , Isquemia Encefálica/fisiopatologia , Feminino , Seguimentos , Humanos , Masculino , Obesidade/complicações , Obesidade/fisiopatologia , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/fisiopatologia
15.
J Acad Nutr Diet ; 115(3): 397-405.e3, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25316108

RESUMO

BACKGROUND: Complementary and alternative medicine (CAM) in the form of vitamin and supplement use is increasingly prevalent in the United States. The interplay between CAM use and use of conventional medications is not well studied. We examined this issue in Old Order Amish (OOA), a population lacking several factors known to influence supplement use, whose culture and barriers to conventional medications may result in high rates of supplement use. OBJECTIVE: We characterized the patterns of supplement use in OOA, including the extent to which CAM use aggregates in families, and assessed whether higher use of supplements is associated with lower medication use. DESIGN: We conducted a cross-sectional study of conventional medications and supplements in 2,372 adult Amish from the Lancaster County, PA, area. Data were collected through face-to-face interviews. Supplements were subcategorized as herbal vs vitamin/mineral supplements. RESULTS: Seventy-seven percent of all Amish adults reported current supplement use, whereas 22% reported medication use. Women used supplements more often and used more supplements than men, and familial aggregation of supplement use was stronger in family pairs involving women. Supplement use was associated with less medication use after controlling for age, sex, body mass index, and self-reported histories of hypertension, diabetes, and hyperlipidemia (adjusted odds ratio [OR] 0.96, 95% CI 0.92 to 1.00; P=0.047). This association was driven primarily by use of herbal supplements (adjusted OR 0.94, 95% CI 0.89 to 0.99; P=0.025) as vitamin/mineral supplements were not associated with different use of medication (adjusted OR 0.99, 95% CI 0.90 to 1.09; P=0.8). In analyses limited to cardiovascular medications and cardiovascular supplements in participants with hyperlipidemia, hypertension, or diabetes, supplement use was not associated with conventional medication use. CONCLUSIONS: OAA, particularly women, take dietary supplements much more frequently than they use conventional medications. Use of herbal supplements is associated with less use of conventional medications, whereas vitamin/mineral supplement use is not.


Assuntos
Amish/estatística & dados numéricos , Suplementos Nutricionais/estatística & dados numéricos , Vitaminas/administração & dosagem , Adulto , Fatores Etários , Idoso de 80 Anos ou mais , Estudos Transversais , Família , Feminino , Humanos , Modelos Logísticos , Masculino , Pennsylvania , Fatores Sexuais , Adulto Jovem
16.
Stroke ; 45(12): 3589-96, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25378430

RESUMO

BACKGROUND AND PURPOSE: NINDS (National Institute of Neurological Disorders and Stroke)-SiGN (Stroke Genetics Network) is an international consortium of ischemic stroke studies that aims to generate high-quality phenotype data to identify the genetic basis of pathogenic stroke subtypes. This analysis characterizes the etiopathogenetic basis of ischemic stroke and reliability of stroke classification in the consortium. METHODS: Fifty-two trained and certified adjudicators determined both phenotypic (abnormal test findings categorized in major pathogenic groups without weighting toward the most likely cause) and causative ischemic stroke subtypes in 16 954 subjects with imaging-confirmed ischemic stroke from 12 US studies and 11 studies from 8 European countries using the web-based Causative Classification of Stroke System. Classification reliability was assessed with blinded readjudication of 1509 randomly selected cases. RESULTS: The distribution of pathogenic categories varied by study, age, sex, and race (P<0.001 for each). Overall, only 40% to 54% of cases with a given major ischemic stroke pathogenesis (phenotypic subtype) were classified into the same final causative category with high confidence. There was good agreement for both causative (κ 0.72; 95% confidence interval, 0.69-0.75) and phenotypic classifications (κ 0.73; 95% confidence interval, 0.70-0.75). CONCLUSIONS: This study demonstrates that pathogenic subtypes can be determined with good reliability in studies that include investigators with different expertise and background, institutions with different stroke evaluation protocols and geographic location, and patient populations with different epidemiological characteristics. The discordance between phenotypic and causative stroke subtypes highlights the fact that the presence of an abnormality in a patient with stroke does not necessarily mean that it is the cause of stroke.


Assuntos
Acidente Vascular Cerebral/classificação , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Institute of Neurological Disorders and Stroke (USA) , Fenótipo , Estados Unidos
17.
Neurology ; 83(18): 1653-60, 2014 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-25261504

RESUMO

OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.


Assuntos
Isquemia Encefálica/diagnóstico , Técnicas e Procedimentos Diagnósticos/normas , Acidente Vascular Cerebral/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/classificação , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , National Institute of Neurological Disorders and Stroke (USA)/normas , Fenótipo , Acidente Vascular Cerebral/classificação , Estados Unidos
18.
Front Genet ; 5: 95, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24808905

RESUMO

Genome-wide association studies (GWAS) are widely applied to identify susceptibility loci for a variety of diseases using genotyping arrays that interrogate known polymorphisms throughout the genome. A particular strength of GWAS is that it is unbiased with respect to specific genomic elements (e.g., coding or regulatory regions of genes), and it has revealed important associations that would have never been suspected based on prior knowledge or assumptions. To date, the discovered SNPs associated with complex human traits tend to have small effect sizes, requiring very large sample sizes to achieve robust statistical power. To address these issues, a number of efficient strategies have emerged for conducting GWAS, including combining study results across multiple studies using meta-analysis, collecting cases through electronic health records, and using samples collected from other studies as controls that have already been genotyped and made publicly available (e.g., through deposition of de-identified data into dbGaP or EGA). In certain scenarios, it may be attractive to use already genotyped controls and divert resources to standardized collection, phenotyping, and genotyping of cases only. This strategy, however, requires that careful attention be paid to the choice of "public controls" and to the comparability of genetic data between cases and the public controls to ensure that any allele frequency differences observed between groups is attributable to locus-specific effects rather than to a systematic bias due to poor matching (population stratification) or differential genotype calling (batch effects). The goal of this paper is to describe some of the potential pitfalls in using previously genotyped control data. We focus on considerations related to the choice of control groups, the use of different genotyping platforms, and approaches to deal with population stratification when cases and controls are genotyped across different platforms.

19.
Stroke ; 45(4): 961-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24619398

RESUMO

BACKGROUND AND PURPOSE: Although the prothrombin G20210A mutation has been implicated as a risk factor for venous thrombosis, its role in arterial ischemic stroke is unclear, particularly among young adults. To address this issue, we examined the association between prothrombin G20210A and ischemic stroke in a white case-control population and additionally performed a meta-analysis. METHODS: From the population-based Genetics of Early Onset Stroke (GEOS) study, we identified 397 individuals of European ancestry aged 15 to 49 years with first-ever ischemic stroke and 426 matched controls. Logistic regression was used to calculate odds ratios (ORs) in the entire population and for subgroups stratified by sex, age, oral contraceptive use, migraine, and smoking status. A meta-analysis of 17 case-control studies (n=2305 cases <55 years) was also performed with and without GEOS data. RESULTS: Within GEOS, the association of the prothrombin G20210A mutation with ischemic stroke did not achieve statistical significance (OR=2.5; 95% confidence interval [CI]=0.9-6.5; P=0.07). However, among adults aged 15 to 42 years (younger than median age), cases were significantly more likely than controls to have the mutation (OR=5.9; 95% CI=1.2-28.1; P=0.03), whereas adults aged 42 to 49 years were not (OR=1.4; 95% CI=0.4-5.1; P=0.94). In our meta-analysis, the mutation was associated with significantly increased stroke risk in adults ≤55 years (OR=1.4; 95% CI=1.1-1.9; P=0.02), with significance increasing with addition of the GEOS results (OR=1.5; 95% CI=1.1-2.0; P=0.005). CONCLUSIONS: The prothrombin G20210A mutation is associated with ischemic stroke in young adults and may have an even stronger association among those with earlier onset strokes. Our finding of a stronger association in the younger young adult population requires replication.


Assuntos
Isquemia Encefálica/genética , Predisposição Genética para Doença/genética , Protrombina/genética , Acidente Vascular Cerebral/genética , Adolescente , Adulto , Idade de Início , Isquemia Encefálica/epidemiologia , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Predisposição Genética para Doença/epidemiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Adulto Jovem
20.
Am J Med Genet C Semin Med Genet ; 166C(1): 76-84, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24616408

RESUMO

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine.


Assuntos
Centros Médicos Acadêmicos/métodos , Farmacogenética/métodos , Inibidores da Agregação de Plaquetas/uso terapêutico , Medicina de Precisão/métodos , Desenvolvimento de Programas/métodos , Centros Médicos Acadêmicos/tendências , Hidrocarboneto de Aril Hidroxilases/genética , Cateterismo Cardíaco/métodos , Citocromo P-450 CYP2C19 , Testes Genéticos/métodos , Humanos , Maryland , Farmacogenética/tendências , Medicina de Precisão/tendências , Desenvolvimento de Programas/estatística & dados numéricos
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