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1.
J Am Heart Assoc ; 10(15): e020187, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34315237

RESUMO

Background This Mendelian randomization study aims to investigate causal associations between genetically predicted insomnia and 14 cardiovascular diseases (CVDs) as well as the potential mediator role of 17 cardiometabolic risk factors. Methods and Results Using genetic association estimates from large genome-wide association studies and UK Biobank, we performed a 2-sample Mendelian randomization analysis to estimate the associations of insomnia with 14 CVD conditions in the primary analysis. Then mediation analysis was conducted to explore the potential mediator role of 17 cardiometabolic risk factors using a network Mendelian randomization design. After correcting for multiple testing, genetically predicted insomnia was consistent significantly positively associated with 9 of 14 CVDs, those odds ratios ranged from 1.13 (95% CI, 1.08-1.18) for atrial fibrillation to 1.24 (95% CI, 1.16-1.32) for heart failure. Moreover, genetically predicted insomnia was consistently associated with higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol, each of which may act as a mediator in the causal pathway from insomnia to several CVD outcomes. Additionally, we found very little evidence to support a causal link between insomnia with abdominal aortic aneurysm, thoracic aortic aneurysm, total cholesterol, low-density lipoprotein cholesterol, glycemic traits, renal function, and heart rate increase during exercise. Finally, we found no evidence of causal associations of genetically predicted body mass index, high-density lipoprotein cholesterol, or triglycerides on insomnia. Conclusions This study provides evidence that insomnia is associated with 9 of 14 CVD outcomes, some of which may be partially mediated by 1 or more of higher body mass index, triglycerides, and lower high-density lipoprotein cholesterol.

2.
Aging (Albany NY) ; 13(12): 16024-16042, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34133324

RESUMO

Prostate adenocarcinoma is one of the leading adult malignancies. Identification of multiple causative biomarkers is necessary and helpful for determining the occurrence and prognosis of prostate adenocarcinoma. We aimed to identify the potential prognostic genes in the prostate adenocarcinoma microenvironment and to estimate the causal effects simultaneously. We obtained the gene expression data of prostate adenocarcinoma from TCGA project and identified the differentially expressed genes based on immune-stromal components. Among these genes, 68 were associated with biochemical recurrence at 3 years after prostatectomy in prostate adenocarcinoma. After adjusting for the minimal sets of confounding covariates, 14 genes (TNFRSF4, ZAP70, ERMN, CXCL5, SPINK6, SLC6A18, CHRM2, TG, CLLU1OS, POSTN, CTSG, NETO1, CEACAM7, and IGLV3-22) related to the microenvironment were identified as prognostic biomarkers using the targeted maximum likelihood estimation. Both the average and individual causal effects were obtained to measure the magnitude of the effect. CIBERSORT and gene set enrichment analyses showed that these prognostic genes were mainly associated with immune responses. POSTN and NETO1 were correlated with androgen receptor expression, a main driver of prostate adenocarcinoma progression. Finally, five genes were validated in another prostate adenocarcinoma cohort (GEO: GSE70770). These findings might lead to the improved prognosis of prostate adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Biomarcadores Tumorais/metabolismo , Recidiva Local de Neoplasia/patologia , Prostatectomia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/cirurgia , Microambiente Tumoral , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Fatores de Confusão Epidemiológicos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/imunologia , Receptores Androgênicos/metabolismo , Reprodutibilidade dos Testes , Células Estromais/metabolismo , Microambiente Tumoral/genética
4.
Biomed Res Int ; 2021: 8893553, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33506048

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease among the elderly and has become a growing global health problem causing great concern. However, the pathogenesis of AD is unclear and no specific therapeutics are available to provide the sustained remission of the disease. In this study, we used comprehensive bioinformatics to determine 158 potential genes, whose expression levels changed between the entorhinal and temporal lobe cortex samples from cognitively normal individuals and patients with AD. Then, we clustered these genes in the protein-protein interaction analysis and identified six significant genes that had more biological functions. Besides, we conducted a drug-gene interaction analysis of module genes in the drug-gene interaction database and obtained 26 existing drugs that might be applied for the prevention and treatment of AD. In addition, a predictive model was built based on the selected genes using different machine learning algorithms to identify individuals with AD. These findings may provide new insights into AD therapy.


Assuntos
Doença de Alzheimer , Fármacos do Sistema Nervoso Central , Biologia Computacional/métodos , Transcriptoma , Algoritmos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Bases de Dados Genéticas , Descoberta de Drogas/métodos , Córtex Entorrinal/química , Córtex Entorrinal/metabolismo , Humanos , Modelos Estatísticos , Mapas de Interação de Proteínas , Lobo Temporal/química , Lobo Temporal/metabolismo
5.
Atherosclerosis ; 320: 112-121, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33485635

RESUMO

BACKGROUND AND AIMS: Some studies reported that mildly elevated serum bilirubin levels were associated with decreased risk of cardiovascular disease (CVD) and diabetes. Whether these are causal relationships remains unclear. This study aims to examine the causal effects of bilirubin on CVD, diabetes and their subtypes. METHODS: The data we used in this study includes individual data from the UK Biobank cohort with 331,002 white British participants, and summary data from published genome wide associations studies (GWAS) findings. We used individual data to perform logistic regression for the observational study and two-stage least squares method for the Mendelian randomization (MR) study. We also performed several traditional MR methods and MR-TRYX by summary data. RESULTS: The observational study supported the association relationships between bilirubin and CVD and diabetes and their subtypes. Results of MR showed strong evidence for negative causal associations of loge total bilirubin with CVD [OR 0.92, 95%CI 0.88-0.95, p-value 2.15 × 10-6], coronary heart disease [OR 0.90, 95%CI 0.85-0.96, p-value 1.54 × 10-3] and hypertensive diseases [OR 0.91, 95%CI 0.88-0.95, p-value 5.89 × 10-6], but no evidence for diabetes [OR 0.94, 95%CI 0.86-1.02, p-value 0.14] and its subtypes. We also obtained similar results for direct bilirubin. We found that blood pressure, cholesterol, C-reactive protein, alcohol and white blood cell count played important roles in the causal pathway from bilirubin to CVD. Two sample MR and sensitivity analyses showed consistent results with one sample MR. CONCLUSIONS: Genetically determined bilirubin was negatively associated with the risk of CVD but had no evident causal association with diabetes in the UK Biobank cohort of white British.


Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Bilirrubina , Bancos de Espécimes Biológicos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Estudos de Coortes , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Reino Unido/epidemiologia
6.
Am J Epidemiol ; 190(3): 468-476, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32830845

RESUMO

The initial aim of environmental epidemiology is to estimate the causal effects of environmental exposures on health outcomes. However, due to lack of enough covariates in most environmental data sets, current methods without enough adjustments for confounders inevitably lead to residual confounding. We propose a negative-control exposure based on a time-series studies (NCE-TS) model to effectively eliminate unobserved confounders using an after-outcome exposure as a negative-control exposure. We show that the causal effect is identifiable and can be estimated by the NCE-TS for continuous and categorical outcomes. Simulation studies indicate unbiased estimation by the NCE-TS model. The potential of NCE-TS is illustrated by 2 challenging applications: We found that living in areas with higher levels of surrounding greenness over 6 months was associated with less risk of stroke-specific mortality, based on the Shandong Ecological Health Cohort during January 1, 2010, to December 31, 2018. In addition, we found that the widely established negative association between temperature and cancer risks was actually caused by numbers of unobserved confounders, according to the Global Open Database from 2003-2012. The proposed NCE-TS model is implemented in an R package (R Foundation for Statistical Computing, Vienna, Austria) called NCETS, freely available on GitHub.


Assuntos
Exposição Ambiental/efeitos adversos , Estudos Epidemiológicos , Causalidade , Fatores de Confusão Epidemiológicos , Humanos , Neoplasias/epidemiologia , Plantas , Acidente Vascular Cerebral/mortalidade , Temperatura
7.
Pediatr Cardiol ; 42(1): 42-46, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33219830

RESUMO

The aim of this study is to evaluate the relationship between maternal single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) gene with plasma homocysteine (HCY) level and offspring congenital heart diseases (CHDs). 338 mothers with offspring CHDs as case group and 306 mothers of normal children as control group were recruited. Their pregnant histories were interviewed by questionnaire and the MTHFR rsl801133 and rsl801131 were genotyped. The case-control analysis was used to find out the relationship between maternal SNPs of MTHFR gene and offspring CHDs. And the plasma HCY concentration of the mothers of CHDs children was detected. This case-case study was intended to find out the relevance between maternal HCY level and SNPs of MTHFR gene. There were significant differences in the gender of children, occupation of mothers, family history with CHDs, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHDs group and control group (P < 0.05). MTHFR rs1801133 was significantly associated with their offspring CHDs in mothers. The polymorphism of maternal MTHFR rs1801133 increased plasma HCY level, especially the homozygous mutation. Besides the environmental factors, our results suggested that the maternal MTHFR rs1801133 polymorphism might be a risk factor of their offspring CHDs, which may be due to the hyperhomocysteinemia by abnormal metabolism of HCY.


Assuntos
Cardiopatias Congênitas/genética , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Criança , Feminino , Genótipo , Humanos , Hiper-Homocisteinemia/epidemiologia , Hiper-Homocisteinemia/genética , Masculino , Mães , Mutação , Gravidez , Fatores de Risco , Inquéritos e Questionários , Adulto Jovem
8.
BMC Genet ; 21(1): 85, 2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32770935

RESUMO

BACKGROUND: Biological pathways play an important role in the occurrence, development and recovery of complex diseases, such as cancers, which are multifactorial complex diseases that are generally caused by mutation of multiple genes or dysregulation of pathways. RESULTS: We propose a path-specific effect statistic (PSE) to detect the differential specific paths under two conditions (e.g. case VS. control groups, exposure Vs. nonexposure groups). In observational studies, the path-specific effect can be obtained by separately calculating the average causal effect of each directed edge through adjusting for the parent nodes of nodes in the specific path and multiplying them under each condition. Theoretical proofs and a series of simulations are conducted to validate the path-specific effect statistic. Applications are also performed to evaluate its practical performances. A series of simulation studies show that the Type I error rates of PSE with Permutation tests are more stable at the nominal level 0.05 and can accurately detect the differential specific paths when comparing with other methods. Specifically, the power reveals an increasing trends with the enlargement of path-specific effects and its effect differences under two conditions. Besides, the power of PSE is robust to the variation of parent or child node of the nodes on specific paths. Application to real data of Glioblastoma Multiforme (GBM), we successfully identified 14 positive specific pathways in mTOR pathway contributing to survival time of patients with GBM. All codes for automatic searching specific paths linking two continuous variables and adjusting set as well as PSE statistic can be found in supplementary materials.  CONCLUSION: The proposed PSE statistic can accurately detect the differential specific pathways contributing to complex disease and thus potentially provides new insights and ways to unlock the black box of disease mechanisms.


Assuntos
Simulação por Computador , Métodos Epidemiológicos , Causalidade , Glioblastoma/genética , Humanos , Modelos Estatísticos , Biologia de Sistemas
9.
BMC Med Res Methodol ; 20(1): 195, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32698801

RESUMO

BACKGROUND: Controlling unobserved confounding still remains a great challenge in observational studies, and a series of strict assumptions of the existing methods usually may be violated in practice. Therefore, it is urgent to put forward a novel method. METHODS: We are interested in the causal effect of an exposure on the outcome, which is always confounded by unobserved confounding. We show that, the causal effect of an exposure on a continuous or categorical outcome is nonparametrically identified through only two independent or correlated available confounders satisfying a non-linear condition on the exposure. Asymptotic theory and variance estimators are developed for each case. We also discuss an extension for more than two binary confounders. RESULTS: The simulations show better estimation performance by our approach in contrast to the traditional regression approach adjusting for observed confounders. A real application is separately applied to assess the effects of Body Mass Index (BMI) on Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Fasting Blood Glucose (FBG), Triglyceride (TG), Total Cholesterol (TC), High Density Lipoprotein (HDL) and Low Density Lipoprotein (LDL) with individuals in Shandong Province, China. Our results suggest that SBP increased 1.60 (95% CI: 0.99-2.93) mmol/L with per 1- kg/m2 higher BMI and DBP increased 0.37 (95% CI: 0.03-0.76) mmol/L with per 1- kg/m2 higher BMI. Moreover, 1- kg/m2 increase in BMI was causally associated with a 1.61 (95% CI: 0.96-2.97) mmol/L increase in TC, a 1.66 (95% CI: 0.91-55.30) mmol/L increase in TG and a 2.01 (95% CI: 1.09-4.31) mmol/L increase in LDL. However, BMI was not causally associated with HDL with effect value - 0.20 (95% CI: - 1.71-1.44). And, the effect value of FBG per 1- kg/m2 higher BMI was 0.56 (95% CI: - 0.24-2.18). CONCLUSIONS: We propose a novel method to control unobserved confounders through double binary confounders satisfying a non-linear condition on the exposure which is easy to access.


Assuntos
Triglicerídeos , Pressão Sanguínea , Índice de Massa Corporal , China , HDL-Colesterol , Humanos
10.
Mol Med ; 26(1): 7, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941463

RESUMO

BACKGROUND AND PURPOSE: Previous studies have found ischemic stroke is associated with atrial fibrillation. However, the causal association between ischemic stroke and atrial fibrillation is not clear. Furthermore, the network relationship among ischemic stroke, atrial fibrillation and its risk factors need further attention. This study aims to examine the potential causal association between ischemic stroke and atrial fibrillation and further to explore potential mediators in the causal pathway from ischemic stroke to atrial fibrillation. METHODS: Summary statistics from the ISGC (case = 10,307 and control = 19,326) were used as ischemic stroke genetic instruments, AFGen Consortium data (case = 65,446 and control = 522,744) were used for atrial fibrillation, and other consortia data were used for potential mediators (fasting insulin, white blood cell count, procalcitonin, systolic and diastolic blood pressure, body mass index, waist circumference, and height). Under the framework of network Mendelian randomization, two-sample Mendelian randomization study was performed using summary statistics from several genome-wide association studies. Inverse-variance weighted method was performed to estimate causal effect. RESULTS: Blood pressure mediates the causal pathways from ischemic stroke to atrial fibrillation. The total odds ratio of ischemic stroke on atrial fibrillation was 1.05 (95% confidence interval [CI], 1.02 to 1.07; P = 1.3 × 10-5). One-unit increase of genetically determined ischemic stroke was associated with 0.02 (DBP: 95% CI, 0.001 to 0.034, P = 0.029; SBP: 95% CI, 0.006 to 0.034, P = 0.003) upper systolic and diastolic blood pressure levels. Higher genetically determined systolic and diastolic blood pressure levels were associated with higher atrial fibrillation risk (DBP: RR, 1.18; 95% CI, 1.03 to 1.35; P = 0.012. SBP: RR, 1.18; 95% CI, 1.01 to 1.38; P = 0.04). Specially, we also found the bidirectional causality between blood pressure and ischemic stroke. CONCLUSIONS: Our study provided a strong evidence that raised blood pressure in stroke patients increases the risk of atrial fibrillation and active acute blood pressure lowering can improve the outcome in ischemic stroke patients.

11.
J Cell Mol Med ; 24(2): 1614-1625, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31829519

RESUMO

Chronic obstructive pulmonary disease (COPD) is a risk factor for the development of lung cancer. The aim of this study was to identify early diagnosis biomarkers for lung squamous cell carcinoma (SQCC) in COPD patients and to determine the potential pathogenetic mechanisms. The GSE12472 data set was downloaded from the Gene Expression Omnibus database. Differentially co-expressed links (DLs) and differentially expressed genes (DEGs) in both COPD and normal tissues, or in both SQCC + COPD and COPD samples were used to construct a dynamic network associated with high-risk genes for the SQCC pathogenetic process. Enrichment analysis was performed based on Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathway analysis. We used the gene expression data and the clinical information to identify the co-expression modules based on weighted gene co-expression network analysis (WGCNA). In total, 205 dynamic DEGs, 5034 DLs and one pathway including CDKN1A, TP53, RB1 and MYC were found to have correlations with the pathogenetic progress. The pathogenetic mechanisms shared by both SQCC and COPD are closely related to oxidative stress, the immune response and infection. WGCNA identified 11 co-expression modules, where magenta and black were correlated with the "time to distant metastasis." And the "surgery due to" was closely related to the brown and blue modules. In conclusion, a pathway that includes TP53, CDKN1A, RB1 and MYC may play a vital role in driving COPD towards SQCC. Inflammatory processes and the immune response participate in COPD-related carcinogenesis.


Assuntos
Carcinoma de Células Escamosas/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/genética , Doença Pulmonar Obstrutiva Crônica/genética , Fumar/efeitos adversos , Fumar/genética , Análise por Conglomerados , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Modelos Biológicos , Mapas de Interação de Proteínas/genética , Reprodutibilidade dos Testes
12.
Ann Transl Med ; 7(11): 234, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31317004

RESUMO

Background: IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide and up to 40% will develop end-stage renal disease (ESRD) within 20 years. However, predicting which patients will progress to ESRD is difficult. The purpose of this study was to develop a predictive model which could accurately predict whether IgAN patients would progress to ESRD. Methods: Six machine learning algorithms were used to predict whether IgAN patients would progress to ESRD: logistic regression, random forest, support vector machine (SVM), decision tree, artificial neural network (ANN), k nearest neighbors (KNN). Nineteen demographic, clinical, pathologic and treatment parameters were used as input for the prediction models. Results: Random forest is best able to predict progression to ESRD. The model had accuracy of 93.97% and sensitivity and specificity of 80.60% and 95.27%, respectively. Conclusions: Machine learning algorithms can effectively predict which patients with IgA nephropathy will progress to end stage renal disease.

13.
PLoS Comput Biol ; 15(6): e1006619, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31206508

RESUMO

Many complex diseases such as cancer are associated with multiple pathological manifestations. Moreover, the therapeutics for their treatments often lead to serious side effects. Thus, it is needed to develop multi-indication therapeutics that can simultaneously target multiple clinical indications of interest and mitigate the side effects. However, conventional one-drug-one-gene drug discovery paradigm and emerging polypharmacology approach rarely tackle the challenge of multi-indication drug design. For the first time, we propose a one-drug-multi-target-multi-indication strategy. We develop a novel structural systems pharmacology platform 3D-REMAP that uses ligand binding site comparison and protein-ligand docking to augment sparse chemical genomics data for the machine learning model of genome-scale chemical-protein interaction prediction. Experimentally validated predictions systematically show that 3D-REMAP outperforms state-of-the-art ligand-based, receptor-based, and machine learning methods alone. As a proof-of-concept, we utilize the concept of drug repurposing that is enabled by 3D-REMAP to design dual-indication anti-cancer therapy. The repurposed drug can demonstrate anti-cancer activity for cancers that do not have effective treatment as well as reduce the risk of heart failure that is associated with all types of existing anti-cancer therapies. We predict that levosimendan, a PDE inhibitor for heart failure, inhibits serine/threonine-protein kinase RIOK1 and other kinases. Subsequent experiments and systems biology analyses confirm this prediction, and suggest that levosimendan is active against multiple cancers, notably lymphoma, through the direct inhibition of RIOK1 and RNA processing pathway. We further develop machine learning models to predict cancer cell-line's and a patient's response to levosimendan. Our findings suggest that levosimendan can be a promising novel lead compound for the development of safe, effective, and precision multi-indication anti-cancer therapy. This study demonstrates the potential of structural systems pharmacology in designing polypharmacology for precision medicine. It may facilitate transforming the conventional one-drug-one-gene-one-disease drug discovery process and single-indication polypharmacology approach into a new one-drug-multi-target-multi-indication paradigm for complex diseases.


Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas/métodos , Farmacogenética/métodos , Inibidores de Fosfodiesterase , Medicina de Precisão/métodos , Biologia Computacional , Humanos
14.
J Infect Dis ; 218(1): 64-74, 2018 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-29741644

RESUMO

Background: Mast cells (MCs) play a key role in immune process response to invading pathogens. Methods: This study assessed the involvement of MCs in controlling Staphylococcus aureus infection in a cutaneous infection model of MC-deficient (KitW-sh/W-sh) mice. Results: KitW-sh/W-sh mice developed significantly larger skin lesions after the cutaneous S. aureus challenge, when compared to wild-type (WT) mice, while MC dysfunction reduced the inflammation response to S. aureus. The levels of tumor necrosis factor (TNF)-α in skin tissues were significantly decreased in KitW-sh/W-sh mice upon infection. Moreover, the exogenous administration of MCs or recombinant TNF-α effectively restored the immune response against S. aureus in KitW-sh/W-sh mice via the recruitment of neutrophils to the infected site. These results indicate that the effects of MC deficiency are largely attributed to the decrease in production of TNF-α in cutaneous S. aureus infection. In addition, S. aureus-induced MC activation was dependent on the c-kit receptor-activated phosphoinositide 3-kinase (PI3K)/AKT/P65-nuclear factor (NF-κB) pathway, which was confirmed by treatment with Masitinib (a c-kit receptor inhibitor), Wortmannin (a PI3K inhibitor), and pyrrolidine dithiocarbamate (a NF-κB inhibitor), respectively. Conclusions: The present study identifies the critical role of MCs in the host defense against S. aureus infection.


Assuntos
Mastócitos/imunologia , Infecções Cutâneas Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções Cutâneas Estafilocócicas/patologia
15.
BMC Med Res Methodol ; 17(1): 177, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29281984

RESUMO

BACKGROUND: Confounders can produce spurious associations between exposure and outcome in observational studies. For majority of epidemiologists, adjusting for confounders using logistic regression model is their habitual method, though it has some problems in accuracy and precision. It is, therefore, important to highlight the problems of logistic regression and search the alternative method. METHODS: Four causal diagram models were defined to summarize confounding equivalence. Both theoretical proofs and simulation studies were performed to verify whether conditioning on different confounding equivalence sets had the same bias-reducing potential and then to select the optimum adjusting strategy, in which logistic regression model and inverse probability weighting based marginal structural model (IPW-based-MSM) were compared. The "do-calculus" was used to calculate the true causal effect of exposure on outcome, then the bias and standard error were used to evaluate the performances of different strategies. RESULTS: Adjusting for different sets of confounding equivalence, as judged by identical Markov boundaries, produced different bias-reducing potential in the logistic regression model. For the sets satisfied G-admissibility, adjusting for the set including all the confounders reduced the equivalent bias to the one containing the parent nodes of the outcome, while the bias after adjusting for the parent nodes of exposure was not equivalent to them. In addition, all causal effect estimations through logistic regression were biased, although the estimation after adjusting for the parent nodes of exposure was nearest to the true causal effect. However, conditioning on different confounding equivalence sets had the same bias-reducing potential under IPW-based-MSM. Compared with logistic regression, the IPW-based-MSM could obtain unbiased causal effect estimation when the adjusted confounders satisfied G-admissibility and the optimal strategy was to adjust for the parent nodes of outcome, which obtained the highest precision. CONCLUSIONS: All adjustment strategies through logistic regression were biased for causal effect estimation, while IPW-based-MSM could always obtain unbiased estimation when the adjusted set satisfied G-admissibility. Thus, IPW-based-MSM was recommended to adjust for confounders set.


Assuntos
Algoritmos , Fatores de Confusão Epidemiológicos , Modelos Logísticos , Modelos Teóricos , Viés , Simulação por Computador , Humanos
16.
BMJ Open ; 7(11): e015640, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29162569

RESUMO

OBJECTIVES: In observational studies, epidemiologists often attempt to estimate the total effect of an exposure on an outcome of interest. However, when the underlying diagram is unknown and limited knowledge is available, dissecting bias performances is essential to estimating the total effect of an exposure on an outcome when mistakenly adjusting for mediators under logistic regression. Through simulation, we focused on six causal diagrams concerning different roles of mediators. Sensitivity analysis was conducted to assess the bias performances of varying across exposure-mediator effects and mediator-outcome effects when adjusting for the mediator. SETTING: Based on the causal relationships in the real world, we compared the biases of varying across the effects of exposure-mediator with those of varying across the effects of mediator-outcome when adjusting for the mediator. The magnitude of the bias was defined by the difference between the estimated effect (using logistic regression) and the total effect of the exposure on the outcome. RESULTS: In four scenarios (a single mediator, two series mediators, two independent parallel mediators or two correlated parallel mediators), the biases of varying across the effects of exposure-mediator were greater than those of varying across the effects of mediator-outcome when adjusting for the mediator. In contrast, in two other scenarios (a single mediator or two independent parallel mediators in the presence of unobserved confounders), the biases of varying across the effects of exposure-mediator were less than those of varying across the effects of mediator-outcome when adjusting for the mediator. CONCLUSIONS: The biases were more sensitive to the variation of effects of exposure-mediator than the effects of mediator-outcome when adjusting for the mediator in the absence of unobserved confounders, while the biases were more sensitive to the variation of effects of mediator-outcome than those of exposure-mediator in the presence of an unobserved confounder.


Assuntos
Viés , Fatores de Confusão Epidemiológicos , Projetos de Pesquisa , Humanos
17.
Neurosci Lett ; 661: 137-142, 2017 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-28982596

RESUMO

Several recent studies suggest that in the human population, a routine, short anesthetic in otherwise healthy infants is void of neurodevelopmental insult. On the other hand, many human retrospective epidemiological studies report evidence of cognitive abnormalities in children after testing those who had different anesthesia-requiring procedures in early childhood. We tested in a rat model whether post-anesthesia stressful environmental factors can contribute to developmental abnormalities that were initiated by a relatively short exposure to sevoflurane, the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABAAR) activity. Postnatal day 6 (P6) male Sprague-Dawley rats were anesthetized with sevoflurane for 60min. To simulate subsequent stress, the animals were subjected to a single maternal separation for 180min at P10. To study the role of GABAAR-mediated depolarization, subgroups of P6 rats received a single injection of the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, prior to initiation of anesthesia with sevoflurane. Rats that were exposed to sevoflurane had decreased hypothalamic K+-2Cl- (KCC2) mRNA level (F(2,13)=3.839, P=0.049), increased NKCC1/KCC2 mRNA ratio (F(2,13)=5.043, P=0.024) and increased corticotropin-releasing hormone (CRH) mRNA level (F(2,12)=9.450, P=0.003) at P10, the age at which maternal separation was imposed. Adult rats, neonatally exposed to a combination of sevoflurane and maternal separation, exhibited increases in the escape latencies greater than animals exposed to sevoflurane only (P=0.012), and only rats in the sevoflurane plus maternal separation group spent significantly less time in the target quadrant during the Morris water maze test (F(4,55)=4.856, P=0.002). Bumetanide ameliorated abnormalities induced by sevoflurane and a combination of sevoflurane plus maternal separation. Neonatal exposure to sevoflurane may sensitize to stressors later in life, and post-exposure stress may exacerbate neurodevelopmental abnormalities even after a relatively short exposure to sevoflurane in rodents. The NKCC1 downregulation prior to exposure to the anesthetic may be therapeutic.


Assuntos
Comportamento Animal/efeitos dos fármacos , Privação Materna , Aprendizagem em Labirinto/efeitos dos fármacos , Éteres Metílicos/farmacologia , Anestésicos Inalatórios/farmacologia , Animais , Animais Recém-Nascidos , Feminino , Ratos Sprague-Dawley , Estudos Retrospectivos , Sevoflurano
18.
Front Cell Neurosci ; 11: 119, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28487636

RESUMO

Mitochondria are supposed to be involved in the early pathogenesis of general anesthesia (GA)-induced neurotoxicity and long-term cognitive deficits in developing brains. However, effective pharmacologic agents targeted on mitochondria during GA exposure are lacking. This study explores the protective effects of mitochondrion-targeted antioxidant elamipretide (SS-31) on mitochondrial morphogenesis and cognition in developing rats exposed to isoflurane. Rat pups at postnatal day (PND) 7 were exposed to 1.5% isoflurane for 6 h following intraperitoneal administration of elamipretide or vehicle with 30 min interval. The hippocampus was immediately removed for biochemical assays. Histopathological studies were conducted at PND 21, and behavioral tests were performed at PND 40 or 60. We found that early exposure to isoflurane caused remarkable reactive oxygen species (ROS) accumulation, mitochondrial deformation and neuronal apoptosis in hippocampus. The injury occurrence ultimately gave rise to long-term cognitive deficits in developing rats. Interestingly, pretreatment with elamipretide not only provided protective effect against oxidative stress and mitochondrial damages, but also attenuated isoflurane-induced cognitive deficits. Our data support the notion that mitochondrial damage is an early and long lasting event of GA-induced injury and suggest that elamipretide might have clinically therapeutic benefits for pediatric patients undertaking GA.

19.
Mol Neurobiol ; 54(5): 3759-3770, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27251428

RESUMO

Parvalbumin (PV) interneurons are critically involved in the cognitive processes. Based on prior investigations that environmental enrichment reverses impaired cognition after anesthetic exposure, we proposed that environmental enrichment protects PV interneurons and thereby improves sevoflurane-induced cognitive impairments. Six-day-old C57BL/6 male mice were exposed to 3 % sevoflurane or 30 % oxygen/air 2 h daily for 3 days from postnatal day 6 (P6) to P8. The mice were randomly allocated to an enriched environment for 2 h daily between P8 and P90 or a standard environment. Western blotting and immunofluorescence were used for determining PV expression in the prefrontal cortex and hippocampus. In another set of experiments, cognitive tests were assessed by the open field test (P41), Morris water maze test (P54-60), and fear conditioning tests (P42-43 and P89-90). Exposure of neonatal mice to sevoflurane resulted in a reduced freezing response in the contextual test at P43 but not P90. The PV expression in these mice was decreased at P9, P14, P28, and P42, but not at ≥P60. No colocalization of caspase-3 and 5-bromo-2-deoxyuridine or caspase-3 and PV was observed, suggesting that caspase-independent pathways may be involved in the mediation of sevoflurane-induced down-regulation of PV. The sevoflurane-exposed mice that were placed in an enriched environment exhibited normal behavior and had PV interneurons that did not differ from those in the control mice at P42-43. Neonatal sevoflurane exposure induces a reduced freezing response in the contextual test at P43 and developmental delays in PV interneurons in the prefrontal cortex and hippocampus. Placement of the sevoflurane-exposed mice in an enriched environment can prevent these abnormalities.


Assuntos
Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Meio Ambiente , Interneurônios/patologia , Éteres Metílicos/administração & dosagem , Éteres Metílicos/efeitos adversos , Parvalbuminas/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo , Interneurônios/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Sevoflurano
20.
Sci Rep ; 6: 37404, 2016 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-27857175

RESUMO

Previous studies have suggested that mitochondrial DNA (mtDNA) copy number was associated with cancer risk. However, no solid conclusion revealed the potential predictive value of mtDNA copy number for cancer prognosis. The present meta-analysis was performed to clarify the problem. Hence, we performed a systematic search in PubMed, EmBase, Web of Science databases independently and a total of eighteen studies comprising 3961 cases satisfied the criteria and finally enrolled. Our results didn't show the association between them but significant heterogeneity in overall analysis (OS: HR = 0.923, 95% CI: 0.653-1.306, p = 0.652; DFS: HR = 0.997, 95% CI: 0.599-1.659, p = 0.99). However, subgroup analysis stratified by sample came to the opposite conclusion. High level mitochondrial DNA copy number in peripheral blood predicted a poor cancer prognosis (OS: HR = 1.624, 95% CI: 1.211-2.177, p = 0.001; DFS: HR = 1.582, 95% CI: 1.026-2.439, p = 0.038) while patients with high level mitochondrial DNA copy number in tumor tissue exhibited better outcomes (OS: HR = 0.604 95% CI: 0.406-0.899, p = 0.013; DFS: HR = 0.593, 95% CI: 0.411-0.857, p = 0.005). These findings were further proved in detailed analyses in blood or tissue subgroup. In conclusion, our study suggested the elevated mtDNA copy number in peripheral blood predicted a poor cancer prognosis while the better outcome was presented among patients with elevated mtDNA copy number in tumor tissue.


Assuntos
DNA Mitocondrial/sangue , Neoplasias/sangue , Prognóstico , Intervalo Livre de Doença , Humanos , Neoplasias/genética , Neoplasias/patologia , Fatores de Risco
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