Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 48
Filtrar
2.
Lung Cancer ; 152: 58-65, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33352384

RESUMO

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; pinteraction = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (pinteraction = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (pinteraction<0.001) and obese categories (pinteraction = 0.004) relative to the normal-BMI category, when compared to male ever-smokers. CONCLUSION: Underweight and obese female ever-smokers were associated with worse outcomes in White-patients. These BMI associations were not observed in Asian-patients and never-smokers. Black-patients had more favorable outcomes in the extremes of BMI when compared to White-patients. Body composition in Black-patients, and NSCLC subtypes more commonly seen in Asian-patients and never-smokers, may account for differences in these BMI-OS relationships.

3.
Addiction ; 115(4): 726-739, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31779050

RESUMO

BACKGROUND AND AIM: Personality functioning is predictive of drug misuse and relapse, yet little is known about the role of personality in engagement with the treatment process. This study aimed to estimate the extent to which broad- and facet-level characteristic adaptations contribute to or hinder treatment engagement, while controlling for psychosocial indicators. DESIGN: Multi-site cross-sectional survey. SETTING: In-patient treatment units covering 80% of residential treatment entries in Greece. PARTICIPANTS: A total of 338 service users, 287 (84.9%) male, 51 (15.1%) female, average age 33.4 years. MEASUREMENTS: Expressions of personality functioning (characteristic adaptations) were assessed using the Severity Indices of Personality Problems (SIPP-118). Treatment engagement was measured using the Client Evaluation of Self and Treatment, in-patient version (CEST). FINDINGS: Dysfunctional levels of relational capacities predicted counselling rapport [ß = 1.50, 95% confidence interval (CI) = 0.326-2.69, P = 0.013], treatment participation (ß = 2.09, 95% CI = 1.15-3.11, P < 0.001) and treatment satisfaction (ß = 1.65, 95% CI = 0.735-2.57, P < 0.001). Counselling rapport was also predicted by dysfunctional levels in self-control (ß = 1.78, 95% CI = 0.899-2.67, P < 0.001), self-reflective functioning at the facet-level (ß = 2.24, 95% CI = 1.01-3.46, P < 0.001) and aggression regulation (ß = 1.43, 95% CI = 0.438-2.42, P = 0.005). Dysfunctional levels on social concordance (ß = -1.90, 95% CI = -2.87 to -0.941, P = 0.001), emotional regulation (ß = 1.90, 95% CI = 0.87-2.92, P < 0.001) and intimacy (ß = 2.04, 95% CI = 1.31-3.05, P < 0.001) were significant predictors of treatment participation. Treatment readiness and desire for help predicted treatment engagement. CONCLUSIONS: In people attending substance use treatment services, maladaptive interpersonal patterns and relational intimacy, emotional dysregulation and impulse control may be associated with low levels of counselling rapport and treatment participation. Low frustration tolerance and aggressive impulses also appeared to predict low participation.

4.
J Thorac Oncol ; 14(9): 1594-1607, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31163278

RESUMO

INTRODUCTION: The relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied. METHODS: Individual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots. RESULTS: Overall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR = 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR = 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR = 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR = 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR = 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets. CONCLUSIONS: Both being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Neoplasias Pulmonares/fisiopatologia , Carcinoma de Pequenas Células do Pulmão/fisiopatologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/mortalidade , Análise de Sobrevida , Adulto Jovem
5.
J Thorac Oncol ; 14(8): 1360-1369, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31009812

RESUMO

INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.


Assuntos
Cromossomos Humanos Par 5 , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Proteínas de Membrana/genética , Telomerase/genética , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla/métodos , Técnicas de Genotipagem/métodos , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
6.
Trials ; 20(1): 151, 2019 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-30819224

RESUMO

BACKGROUND: In proportionate or adaptive interventions, the dose or intensity can be adjusted based on individual need at predefined decision stages during the delivery of the intervention. The development of such interventions may require an evaluation of the effectiveness of the individual stages in addition to the whole intervention. However, evaluating individual stages of an intervention has various challenges, particularly the statistical design and analysis. This review aimed to identify the use of trials of proportionate interventions and how they are being designed and analysed in current practice. METHODS: We searched MEDLINE, Web of Science and PsycINFO for articles published between 2010 and 2015 inclusive. We considered trials of proportionate interventions in all fields of research. For each trial, its aims, design and analysis were extracted. The data synthesis was conducted using summary statistics and a narrative format. RESULTS: Our review identified 44 proportionate intervention trials, comprising 28 trial results, 13 protocols and three secondary analyses. These were mostly described as stepped care (n=37) and mainly focussed on mental health research (n=30). The other studies were aimed at finding an optimal adaptive treatment strategy (n=7) in a variety of therapeutic areas. Further terminology used included adaptive intervention, staged intervention, sequentially multiple assignment trial or a two-phase design. The median number of decision stages in the interventions was two and only one study explicitly evaluated the effect of the individual stages. CONCLUSIONS: Trials of proportionate staged interventions are being used predominantly within the mental health field. However, few studies consider the different stages of the interventions, either at the design or the analysis phase, and how they may interact with one another. There is a need for further guidance on the design, analyses and reporting across trials of proportionate interventions. TRIAL REGISTRATION: Prospero, CRD42016033781. Registered on 2 February 2016.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Interpretação Estatística de Dados , Determinação de Ponto Final/estatística & dados numéricos , Modelos Estatísticos , Projetos de Pesquisa/estatística & dados numéricos , Humanos , Resultado do Tratamento
7.
Carcinogenesis ; 40(3): 432-440, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-30590402

RESUMO

DNase I hypersensitive sites (DHS) are abundant in regulatory elements, such as promoter, enhancer and transcription factor binding sites. Many studies have revealed that disease-associated variants were concentrated in DHS-related regions. However, limited studies are available on the roles of DHS-related variants in lung cancer. In this study, we performed a large-scale case-control study with 20 871 lung cancer cases and 15 971 controls to evaluate the associations between regulatory genetic variants in DHS and lung cancer susceptibility. The expression quantitative trait loci (eQTL) analysis and pathway-enrichment analysis were performed to identify the possible target genes and pathways. In addition, we performed motif-based analysis to explore the lung-cancer-related motifs using sequence kernel association test. Two novel variants, rs186332 in 20q13.3 (C>T, odds ratio [OR] = 1.17, 95% confidence interval [95% CI]: 1.10-1.24, P = 8.45 × 10-7) and rs4839323 in 1p13.2 (T>C, OR = 0.92, 95% CI: 0.89-0.95, P = 1.02 × 10-6) showed significant association with lung cancer risk. The eQTL analysis suggested that these two SNPs might regulate the expression of MRGBP and SLC16A1, respectively. What's more, the expression of both MRGBP and SLC16A1 was aberrantly elevated in lung tumor tissues. The motif-based analysis identified 10 motifs related to the risk of lung cancer (P < 1.71 × 10-4). Our findings suggested that variants in DHS might modify lung cancer susceptibility through regulating the expression of surrounding genes. This study provided us a deeper insight into the roles of DHS-related genetic variants for lung cancer.


Assuntos
Desoxirribonuclease I/metabolismo , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas
8.
Int J Epidemiol ; 48(3): 751-766, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30059977

RESUMO

BACKGROUND: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses. METHODS: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects. RESULTS: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk. CONCLUSIONS: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.


Assuntos
Adenocarcinoma de Pulmão/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Leucócitos/metabolismo , Neoplasias Pulmonares/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Homeostase do Telômero/genética , Telômero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5/genética , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade
9.
BMJ Open ; 8(12): e026906, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30573493

RESUMO

INTRODUCTION: Behavioural and mental disorders have become a public health crisis and by 2020 may surpass physical illness as a major cause of disability. Early prevention is key. Two Incredible Years (IY) parent programmes that aim to enhance child well-being and development, IY Infant and IY Toddler, will be delivered and evaluated in a proportionate universal intervention model called Enhancing Social-Emotional Health and Wellbeing in the Early Years (E-SEE) Steps. The main research question is: Does E-SEE Steps enhance child social emotional well-being at 20 months when compared with services as usual? METHODS AND ANALYSIS: E-SEE Steps will be delivered in community settings by Early Years Children's Services and/or Public Health staff across local authorities. Parents of children aged 8 weeks or less, identified by health visitors, children's centre staff or self-referral, are eligible for participation in the trial. The randomisation allocation ratio is 5:1 (intervention to control). All intervention parents will receive an Incredible Years Infant book (universal level), and may be offered the Infant and/or Toddler group-based programme/s-based on parent depression scores on the Patient Health Questionnaire or child social emotional well-being scores on the Ages and Stages Questionnaire: Social Emotional, Second Edition (ASQ:SE-2). Control group parents will receive services as usual. A process and economic evaluation are included. The primary outcome for the study is social emotional well-being, assessed at 20 months, using the ASQ:SE-2. Intention-to-treat and per protocol analyses will be conducted. Clustering and hierarchical effects will be accounted for using linear mixed models. ETHICS AND DISSEMINATION: Ethical approvals have been obtained from the University of York Education Ethics Committee (ref: FC15/03, 10 August 2015) and UK NHS REC 5 (ref: 15/WA/0178, 22 May 2015. The current protocol is Version 9, 26 February 2018. The sponsor of the trial is the University of York. Dissemination of findings will be via peer-reviewed journals, conference presentations and public events. TRIAL REGISTRATION NUMBER: ISRCTN11079129; Pre-results.


Assuntos
Bem-Estar da Criança , Emoções , Saúde Mental , Pais/educação , Desenvolvimento Infantil , Pré-Escolar , Análise Custo-Benefício , Humanos , Lactente , Transtornos Mentais/prevenção & controle , Relações Pais-Filho , Ensaios Clínicos Pragmáticos como Assunto , Inquéritos e Questionários , Reino Unido
10.
BMC Med Res Methodol ; 18(1): 105, 2018 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-30314463

RESUMO

BACKGROUND: In individually randomised trials we might expect interventions delivered in groups or by care providers to result in clustering of outcomes for participants treated in the same group or by the same care provider. In partially nested randomised controlled trials (pnRCTs) this clustering only occurs in one trial arm, commonly the intervention arm. It is important to measure and account for between-cluster variability in trial design and analysis. We compare analysis approaches for pnRCTs with continuous outcomes, investigating the impact on statistical inference of cluster sizes, coding of the non-clustered arm, intracluster correlation coefficient (ICCs), and differential variance between intervention and control arm, and provide recommendations for analysis. METHODS: We performed a simulation study assessing the performance of six analysis approaches for a two-arm pnRCT with a continuous outcome. These include: linear regression model; fully clustered mixed-effects model with singleton clusters in control arm; fully clustered mixed-effects model with one large cluster in control arm; fully clustered mixed-effects model with pseudo clusters in control arm; partially nested homoscedastic mixed effects model, and partially nested heteroscedastic mixed effects model. We varied the cluster size, number of clusters, ICC, and individual variance between the two trial arms. RESULTS: All models provided unbiased intervention effect estimates. In the partially nested mixed-effects models, methods for classifying the non-clustered control arm had negligible impact. Failure to account for even small ICCs resulted in inflated Type I error rates and over-coverage of confidence intervals. Fully clustered mixed effects models provided poor control of the Type I error rates and biased ICC estimates. The heteroscedastic partially nested mixed-effects model maintained relatively good control of Type I error rates, unbiased ICC estimation, and did not noticeably reduce power even with homoscedastic individual variances across arms. CONCLUSIONS: In general, we recommend the use of a heteroscedastic partially nested mixed-effects model, which models the clustering in only one arm, for continuous outcomes similar to those generated under the scenarios of our simulations study. However, with few clusters (3-6), small cluster sizes (5-10), and small ICC (≤0.05) this model underestimates Type I error rates and there is no optimal model.


Assuntos
Simulação por Computador , Interpretação Estatística de Dados , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Algoritmos , Análise por Conglomerados , Humanos , Modelos Lineares , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/normas , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Reprodutibilidade dos Testes , Projetos de Pesquisa/normas , Tamanho da Amostra
11.
Nat Commun ; 9(1): 3927, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30254314

RESUMO

Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA-tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.


Assuntos
Mapeamento Cromossômico , Predisposição Genética para Doença/genética , Neoplasias Pulmonares/genética , Complexo Principal de Histocompatibilidade/genética , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Antígenos HLA/genética , Humanos , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Peptídeos/genética , Polimorfismo de Nucleotídeo Único
12.
BMJ Open ; 8(8): e025031, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-30121618

RESUMO

INTRODUCTION: Specific phobias (intense, enduring fears of an object or situation that lead to avoidance and severe distress) are highly prevalent among children and young people. Cognitive-behavioural therapy (CBT) is a well-established, effective intervention, but it can be time consuming and costly because it is routinely delivered over multiple sessions during several months. Alternative methods of treating severe and debilitating phobias in children are needed, like one-session treatment (OST), to reduce time and cost, and to prevent therapeutic drift and help children recover quickly. Our study explores whether (1) outcomes with OST are 'no worse' than outcomes with multisession CBT, (2) OST is acceptable to children, their parents and the practitioners who use it and (3) OST offers good value for money to the National Health Service (NHS) and to society. METHOD: A pragmatic, non-inferiority, randomised controlled trial will compare OST with multisession CBT-based therapy on their clinical and cost-effectiveness. The primary clinical outcome is a standardised behavioural task of approaching the feared stimulus at 6 months postrandomisation. The outcomes for the within-trial cost-effectiveness analysis are quality-adjusted life years based on EQ-5D-Y, and individual-level costs based of the intervention and use of health and social service care. A nested qualitative evaluation will explore children's, parents' and practitioners' perceptions and experiences of OST. A total of 286 children, 7-16 years old, with DSM-IV diagnoses of specific phobia will be recruited via gatekeepers in the NHS, schools and voluntary youth services, and via public adverts. ETHICS AND DISSEMINATION: The trial received ethical approval from North East and York Research Ethics Committee (Reference: 17/NE/0012). Dissemination plans include publications in peer-reviewed journals, presentations in relevant research conferences, local research symposia and seminars for children and their families, and for professionals and service managers. TRIAL REGISTRATION NUMBER: ISRCTN19883421;Pre-results.


Assuntos
Terapia Cognitivo-Comportamental/métodos , Transtornos Fóbicos/terapia , Adolescente , Criança , Protocolos Clínicos , Terapia Cognitivo-Comportamental/economia , Análise Custo-Benefício , Feminino , Humanos , Masculino , Transtornos Fóbicos/economia , Resultado do Tratamento
13.
Nat Commun ; 9(1): 3221, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30104567

RESUMO

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.


Assuntos
Cromossomos Humanos Par 15/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Reprodutibilidade dos Testes , Fatores de Risco , Fumar/efeitos adversos , Adulto Jovem
14.
Int Arch Occup Environ Health ; 91(8): 937-950, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29971594

RESUMO

PURPOSE: Radon is a risk factor for lung cancer and uranium miners are more exposed than the general population. A genome-wide interaction analysis was carried out to identify genomic loci, genes or gene sets that modify the susceptibility to lung cancer given occupational exposure to the radioactive gas radon. METHODS: Samples from 28 studies provided by the International Lung Cancer Consortium were pooled with samples of former uranium miners collected by the German Federal Office of Radiation Protection. In total, 15,077 cases and 13,522 controls, all of European ancestries, comprising 463 uranium miners were compared. The DNA of all participants was genotyped with the OncoArray. We fitted single-marker and in multi-marker models and performed an exploratory gene-set analysis to detect cumulative enrichment of significance in sets of genes. RESULTS: We discovered a genome-wide significant interaction of the marker rs12440014 within the gene CHRNB4 (OR = 0.26, 95% CI 0.11-0.60, p = 0.0386 corrected for multiple testing). At least suggestive significant interaction of linkage disequilibrium blocks was observed at the chromosomal regions 18q21.23 (p = 1.2 × 10-6), 5q23.2 (p = 2.5 × 10-6), 1q21.3 (p = 3.2 × 10-6), 10p13 (p = 1.3 × 10-5) and 12p12.1 (p = 7.1 × 10-5). Genes belonging to the Gene Ontology term "DNA dealkylation involved in DNA repair" (GO:0006307; p = 0.0139) or the gene family HGNC:476 "microRNAs" (p = 0.0159) were enriched with LD-blockwise significance. CONCLUSION: The well-established association of the genomic region 15q25 to lung cancer might be influenced by exposure to radon among uranium miners. Furthermore, lung cancer susceptibility is related to the functional capability of DNA damage signaling via ubiquitination processes and repair of radiation-induced double-strand breaks by the single-strand annealing mechanism.


Assuntos
Carcinógenos Ambientais/toxicidade , Neoplasias Pulmonares/genética , Neoplasias Induzidas por Radiação/genética , Proteínas do Tecido Nervoso/genética , Doenças Profissionais/genética , Radônio/toxicidade , Receptores Nicotínicos/genética , Estudos de Casos e Controles , Dano ao DNA/efeitos da radiação , Feminino , Marcadores Genéticos/efeitos da radiação , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mineração , Exposição Ocupacional/efeitos adversos , Fatores de Risco , Ubiquitinação/efeitos da radiação , Urânio
15.
Elife ; 72018 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-29319501

RESUMO

Many studies in the biomedical research literature report analyses that fail to recognise important data dependencies from multilevel or complex experimental designs. Statistical inferences resulting from such analyses are unlikely to be valid and are often potentially highly misleading. Failure to recognise this as a problem is often referred to in the statistical literature as a unit of analysis (UoA) issue. Here, by analysing two example datasets in a simulation study, we demonstrate the impact of UoA issues on study efficiency and estimation bias, and highlight where errors in analysis can occur. We also provide code (written in R) as a resource to help researchers undertake their own statistical analyses.


Assuntos
Pesquisa Biomédica/métodos , Bioestatística/métodos , Interpretação Estatística de Dados
16.
PLoS One ; 12(9): e0185660, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28957450

RESUMO

Obesity and cigarette smoking are correlated through complex relationships. Common genetic causes may contribute to these correlations. In this study, we selected 241 loci potentially associated with body mass index (BMI) based on the Genetic Investigation of ANthropometric Traits (GIANT) consortium data and calculated a BMI genetic risk score (BMI-GRS) for 17,037 individuals of European descent from the Oncoarray Project of the International Lung Cancer Consortium (ILCCO). Smokers had a significantly higher BMI-GRS than never-smokers (p = 0.016 and 0.010 before and after adjustment for BMI, respectively). The BMI-GRS was also positively correlated with pack-years of smoking (p<0.001) in smokers. Based on causal network inference analyses, seven and five of 241 SNPs were classified to pleiotropic models for BMI/smoking status and BMI/pack-years, respectively. Among them, three and four SNPs associated with smoking status and pack-years (p<0.05), respectively, were followed up in the ever-smoking data of the Tobacco, Alcohol and Genetics (TAG) consortium. Among these seven candidate SNPs, one SNP (rs11030104, BDNF) achieved statistical significance after Bonferroni correction for multiple testing, and three suggestive SNPs (rs13021737, TMEM18; rs11583200, ELAVL4; and rs6990042, SGCZ) achieved a nominal statistical significance. Our results suggest that there is a common genetic component between BMI and smoking, and pleiotropy analysis can be useful to identify novel genetic loci of complex phenotypes.


Assuntos
Obesidade/genética , Polimorfismo de Nucleotídeo Único , Fumar/genética , Idoso , Índice de Massa Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
17.
Nat Genet ; 49(7): 1126-1132, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28604730

RESUMO

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.


Assuntos
Estudo de Associação Genômica Ampla , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Adulto , Idoso , Mapeamento Cromossômico , Grupo com Ancestrais do Continente Europeu/genética , Saúde da Família , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fumar/epidemiologia , Homeostase do Telômero/genética
18.
BMJ Open ; 7(1): e014324, 2017 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-28087556

RESUMO

OBJECTIVES: Management of anticoagulated patients after head injury is unclear due to lack of robust evidence. This study aimed to determine the adverse outcome rate in these patients and identify risk factors associated with poor outcome. DESIGN: Multicentre, observational study using routine patient records. SETTING: 33 emergency departments in England and Scotland. PARTICIPANTS: 3566 adults (aged ≥16 years) who had suffered blunt head injury and were currently taking warfarin. MAIN OUTCOME MEASURES: Primary outcome measure was rate of adverse outcome defined as death or neurosurgery following initial injury, clinically significant CT scan finding or reattendance with related complication within 10 weeks of initial hospital attendance. Secondary objectives included identifying risk factors for adverse outcome using univariable and multivariable analyses. RESULTS: Clinical data available for 3534/3566 patients (99.1%), median age 79 years; mean initial international normalised ratio (INR) 2.67 (SD 1.34); 81.2% Glasgow Coma Scale (GCS) 15: 59.8% received a CT scan with significant head injury-related finding in 5.4% (n=208); 0.5% underwent neurosurgery; 1.2% patients suffered a head injury-related death. Overall adverse outcome rate was 5.9% (95% CI 5.2% to 6.7%). Patients with GCS=15 and no associated symptoms had lowest risk of adverse outcome (risk 2.7%; 95% CI 2.1 to 3.6). Patients with GCS=15 multivariable analysis (using imputation) found risk of adverse outcome to increase when reporting at least one associated symptom: vomiting (relative risk (RR) 1.8; 95% CI 1.0 to 3.4), amnesia (RR 3.5; 95% CI 2.1 to 5.7), headache (RR 1.3; 95% CI 0.8 to 2.2), loss of consciousness (RR 1.75; 95% CI 1.0 to 3.0). INR measurement did not predict adverse outcome in patients with GCS=15 (RR 1.1; 95% CI 1.0 to 1.2). CONCLUSIONS: In alert warfarinised patients following head injury, the presence of symptoms is associated with greater risk of adverse outcome. Those with GCS=15 and no symptoms are a substantial group and have a low risk of adverse outcome. TRIAL REGISTRATION NUMBER: NCT02461498.


Assuntos
Anticoagulantes/efeitos adversos , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Traumatismos Cranianos Fechados/diagnóstico por imagem , Varfarina/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amnésia/epidemiologia , Lesões Encefálicas Traumáticas/mortalidade , Serviço Hospitalar de Emergência , Feminino , Escala de Coma de Glasgow , Traumatismos Cranianos Fechados/mortalidade , Cefaleia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Tomografia Computadorizada por Raios X , Inconsciência/epidemiologia , Vômito/epidemiologia , Adulto Jovem
19.
Heart ; 103(8): 586-591, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27899428

RESUMO

OBJECTIVES: Previous studies have shown that smokers presented with ST-segment elevation myocardial infarction (STEMI) a decade earlier than non-smokers. However, no account has been made for population smoking trends, an important deficit addressed by this study. METHODS: The combination of admission data on patients with acute STEMI undergoing percutaneous coronary intervention and demographic data supplied by the Office for National Statistics for the South Yorkshire population between 2009-2012 were analysed to generate incidence rates and rate ratios (RR) to quantify the relative risk of STEMI from smoking, overall and by age group. RESULTS: There were 1795 STEMI patients included of which 72.9% were male. 68 patients were excluded as they had no smoking status recorded, leaving 48.5% of the remaining population as current smokers, 27.2% ex-smokers and 24.3% never smokers. Smokers were over-represented with overall smoking prevalence in South Yorkshire calculated at 22.4%. The incidence of STEMI in smokers aged under 50, 50-65 and over 65 years was 59.7, 316.9 and 331.0 per 100 000 patient years at risk compared to 7.0, 60.9 and 106.8 for the combined group of ex- and never smokers. This gave smokers under the age of 50 years an 8.47 (95% CI 6.80 to 10.54) increase in rate compared to non-smokers of the same age, with the 50-65 and over 65 age groups having RRs of 5.20 (95% CI 4.76 to 5.69) and 3.10 (95% CI 2.67 to 3.60), respectively. CONCLUSIONS: Smoking was associated with an eightfold increased risk of acute STEMI in younger smokers, when compared to ex- and never smokers. Further efforts to reduce smoking in the youngest are needed.


Assuntos
Infarto do Miocárdio com Supradesnível do Segmento ST/epidemiologia , Fumar/epidemiologia , Distribuição por Idade , Idade de Início , Idoso , Distribuição de Qui-Quadrado , Inglaterra/epidemiologia , Feminino , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prevalência , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Fumar/efeitos adversos , Fumar/tendências , Fatores de Tempo
20.
BMJ Open ; 6(12): e013742, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27974370

RESUMO

OBJECTIVES: It is not currently clear whether all anticoagulated patients with a head injury should receive CT scanning or only those with evidence of traumatic brain injury (eg, loss of consciousness or amnesia). We aimed to determine the cost-effectiveness of CT for all compared with selective CT use for anticoagulated patients with a head injury. DESIGN: Decision-analysis modelling of data from a multicentre observational study. SETTING: 33 emergency departments in England and Scotland. PARTICIPANTS: 3566 adults (aged ≥16 years) who had suffered blunt head injury, were taking warfarin and underwent selective CT scanning. MAIN OUTCOME MEASURES: Estimated expected benefits in terms of quality-adjusted life years (QALYs) were the entire cohort to receive a CT scan; estimated increased costs of CT and also the potential cost implications associated with patient survival and improved health. These values were used to estimate the cost per QALY of implementing a strategy of CT for all patients compared with observed practice based on guidelines recommending selective CT use. RESULTS: Of the 1420 of 3534 patients (40%) who did not receive a CT scan, 7 (0.5%) suffered a potentially avoidable head injury-related adverse outcome. If CT scanning had been performed in all patients, appropriate treatment could have gained 3.41 additional QALYs but would have incurred £193 149 additional treatment costs and £130 683 additional CT costs. The incremental cost-effectiveness ratio of £94 895/QALY gained for unselective compared with selective CT use is markedly above the threshold of £20-30 000/QALY used by the UK National Institute for Care Excellence to determine cost-effectiveness. CONCLUSIONS: CT scanning for all anticoagulated patients with head injury is not cost-effective compared with selective use of CT scanning based on guidelines recommending scanning only for those with evidence of traumatic brain injury. TRIAL REGISTRATION NUMBER: NCT 02461498.


Assuntos
Análise Custo-Benefício , Traumatismos Craniocerebrais/diagnóstico por imagem , Técnicas de Apoio para a Decisão , Tomografia Computadorizada por Raios X/economia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Traumatismos Craniocerebrais/tratamento farmacológico , Serviço Hospitalar de Emergência/organização & administração , Inglaterra , Feminino , Escala de Resultado de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Anos de Vida Ajustados por Qualidade de Vida , Escócia , Varfarina/uso terapêutico , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...