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1.
Artigo em Inglês | MEDLINE | ID: mdl-34788659

RESUMO

BACKGROUND: Little is known about the relationship of longitudinal growth trajectory in early life with asthma development, particularly in infants with bronchiolitis (a high-risk population). OBJECTIVE: Among infants with bronchiolitis, we aimed to identify growth trajectory profiles and to determine their longitudinal relationship with the risk for developing childhood asthma. METHODS: A multicenter prospective study enrolled infants (aged <1 year) hospitalized for bronchiolitis. We identified growth trajectory profiles-derived from BMI-for-age at ages 0, 6, 12, 15, 18, 24, and 36 months by using a longitudinal clustering method. We examined associations between growth trajectory profiles and asthma development by age 5 years. RESULTS: The analytic cohort consists of 880 infants hospitalized for bronchiolitis (median age, 3 months). Overall, 26% developed asthma by age 5 years. The longitudinal clustering identified five distinct profiles: persistent low growth (27%), normative growth (33%), transient overweight (21%), late-onset overweight (16%), and persistent obesity (3%) profiles. In multivariable model, compared to children with a normative profile, those with a persistent obesity profile had significantly higher risks of developing asthma (24% vs. 38%, OR 2.55, 95%CI 1.07-6.09, P=0.03). Among children with a persistent obesity profile, those without allergic predisposition had significantly higher risks of asthma (OR 3.02, 95%CI 1.05-8.64, P=0.04 in the non-parental allergic history group; OR 3.18, 95%CI 1.02-9.92, P=0.047 in the non-IgE sensitization group) while those with allergic predisposition were not at increased risk. CONCLUSIONS: This multicenter cohort study of infants with bronchiolitis demonstrated distinct growth trajectory profiles that have differential risks for developing asthma.

2.
Metabolism ; 125: 154915, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34678258

RESUMO

BACKGROUND: Tricarboxylic acid (TCA) cycle deregulation may predispose to cardiovascular diseases, but the role of TCA cycle-related metabolites in the development of atrial fibrillation (AF) and heart failure (HF) remains unexplored. This study sought to investigate the association of TCA cycle-related metabolites with risk of AF and HF. METHODS: We used two nested case-control studies within the PREDIMED study. During a mean follow-up for about 10 years, 512 AF and 334 HF incident cases matched by age (±5 years), sex and recruitment center to 616 controls and 433 controls, respectively, were included in this study. Baseline plasma levels of citrate, aconitate, isocitrate, succinate, malate and d/l-2-hydroxyglutarate were measured with liquid chromatography-tandem mass spectrometry. Multivariable conditional logistic regression models were fitted to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for metabolites and the risk of AF or HF. Potential confounders included smoking, family history of premature coronary heart disease, physical activity, alcohol intake, body mass index, intervention groups, dyslipidemia, hypertension, type 2 diabetes and medication use. RESULTS: Comparing extreme quartiles of metabolites, elevated levels of succinate, malate, citrate and d/l-2-hydroxyglutarate were associated with a higher risk of AF [ORQ4 vs. Q1 (95% CI): 1.80 (1.21-2.67), 2.13 (1.45-3.13), 1.87 (1.25-2.81) and 1.95 (1.31-2.90), respectively]. One SD increase in aconitate was directly associated with AF risk [OR (95% CI): 1.16 (1.01-1.34)]. The corresponding ORs (95% CI) for HF comparing extreme quartiles of malate, aconitate, isocitrate and d/l-2-hydroxyglutarate were 2.15 (1.29-3.56), 2.16 (1.25-3.72), 2.63 (1.56-4.44) and 1.82 (1.10-3.04), respectively. These associations were confirmed in an internal validation, except for aconitate and AF. CONCLUSION: These findings underscore the potential role of the TCA cycle in the pathogenesis of cardiac outcomes.

3.
Elife ; 102021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34515027

RESUMO

Background: Identifying environmentally responsive genetic loci where DNA methylation is associated with coronary heart disease (CHD) may reveal novel pathways or therapeutic targets for CHD. We conducted the first prospective epigenome-wide analysis of DNA methylation in relation to incident CHD in the Asian population. Methods: We did a nested case-control study comprising incident CHD cases and 1:1 matched controls who were identified from the 10 year follow-up of the China Kadoorie Biobank. Methylation level of baseline blood leukocyte DNA was measured by Infinium Methylation EPIC BeadChip. We performed the single cytosine-phosphate-guanine (CpG) site association analysis and network approach to identify CHD-associated CpG sites and co-methylation gene module. Results: After quality control, 982 participants (mean age 50.1 years) were retained. Methylation level at 25 CpG sites across the genome was associated with incident CHD (genome-wide false discovery rate [FDR] < 0.05 or module-specific FDR < 0.01). One SD increase in methylation level of identified CpGs was associated with differences in CHD risk, ranging from a 47 % decrease to a 118 % increase. Mediation analyses revealed 28.5 % of the excessed CHD risk associated with smoking was mediated by methylation level at the promoter region of ANKS1A gene (P for mediation effect = 0.036). Methylation level at the promoter region of SNX30 was associated with blood pressure and subsequent risk of CHD, with the mediating proportion to be 7.7 % (P = 0.003) via systolic blood pressure and 6.4 % (P = 0.006) via diastolic blood pressure. Network analysis revealed a co-methylation module associated with CHD. Conclusions: We identified novel blood methylation alterations associated with incident CHD in the Asian population and provided evidence of the possible role of epigenetic regulations in the smoking- and blood pressure-related pathways to CHD risk. Funding: This work was supported by National Natural Science Foundation of China (81390544 and 91846303). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (202922/Z/16/Z, 088158/Z/09/Z, 104085/Z/14/Z), grant (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) from the National Key R&D Program of China, and Chinese Ministry of Science and Technology (2011BAI09B01).

4.
JAMA ; 326(9): 839-850, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34547084

RESUMO

Importance: School and classroom allergens and particles are associated with asthma morbidity, but the benefit of environmental remediation is not known. Objective: To determine whether use of a school-wide integrated pest management (IPM) program or high-efficiency particulate air (HEPA) filter purifiers in the classrooms improve asthma symptoms in students with active asthma. Design, Setting, and Participants: Factorial randomized clinical trial of a school-wide IPM program and HEPA filter purifiers in the classrooms was conducted from 2015 to 2020 (School Inner-City Asthma Intervention Study). There were 236 students with active asthma attending 41 participating urban elementary schools located in the Northeastern US who were randomized to IPM by school and HEPA filter purifiers by classroom. The date of final follow-up was June 20, 2020. Interventions: The school-wide IPM program consisted of application of rodenticide, sealing entry points, trap placement, targeted cleaning, and brief educational handouts for school staff. Infestation was assessed every 3 months, with additional treatments as needed. Control schools received no IPM, cleaning, or education. Classroom portable HEPA filter purifiers were deployed and the filters were changed every 3 months. Control classrooms received sham HEPA filters that looked and sounded like active HEPA filter purifiers. Randomization was done independently (split-plot design), with matching by the number of enrolled students to ensure a nearly exact 1:1 student ratio for each intervention with 118 students randomized to each group. Participants, investigators, and those assessing outcomes were blinded to the interventions. Main Outcomes and Measures: The primary outcome was the number of symptom-days with asthma during a 2-week period. Symptom-days were assessed every 2 months during the 10 months after randomization. Results: Among the 236 students who were randomized (mean age, 8.1 [SD, 2.0] years; 113 [48%] female), all completed the trial. At baseline, the 2-week mean was 2.2 (SD, 3.9) symptom-days with asthma and 98% of the classrooms had detectable levels of mouse allergen. The results were pooled because there was no statistically significant difference between the 2 interventions (P = .18 for interaction). During a 2-week period, the mean was 1.5 symptom-days with asthma after use of the school-wide IPM program vs 1.9 symptom-days after no IPM across the school year (incidence rate ratio, 0.71 [95% CI, 0.38-1.33]), which was not statistically significantly different. During a 2-week period, the mean was 1.6 symptom-days with asthma after use of HEPA filter purifiers in the classrooms vs 1.8 symptom-days after use of sham HEPA filter purifiers across the school year (incidence rate ratio, 1.47 [95% CI, 0.79-2.75]), which was not statistically significantly different. There were no intervention-related adverse events. Conclusions and Relevance: Among children with active asthma, use of a school-wide IPM program or classroom HEPA filter purifiers did not significantly reduce symptom-days with asthma. However, interpretation of the study findings may need to consider allergen levels, particle exposures, and asthma symptoms at baseline. Trial Registration: ClinicalTrials.gov Identifier: NCT02291302.


Assuntos
Filtros de Ar , Poluição do Ar em Ambientes Fechados/prevenção & controle , Asma/prevenção & controle , Exposição Ambiental/prevenção & controle , Controle de Roedores , Instituições Acadêmicas , Poluição do Ar em Ambientes Fechados/efeitos adversos , Alérgenos/análise , Criança , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Masculino , Rodenticidas
5.
Artigo em Inglês | MEDLINE | ID: mdl-34413117

RESUMO

INTRODUCTION: We investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults. RESEARCH DESIGN AND METHODS: We used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40-75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates. RESULTS: Six metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS. CONCLUSIONS: Among Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.


Assuntos
Diabetes Mellitus Tipo 2 , Adulto , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Hispano-Americanos , Humanos , Estudos Longitudinais
6.
Environ Int ; 157: 106800, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34358915

RESUMO

BACKGROUND: Neural tube defects are a pressing public health concern despite advances in prevention from folic acid-based strategies. Numerous chemicals, in particular arsenic, have been associated with neural tube defects in animal models and could influence risk in humans. OBJECTIVES: We investigated the relationship between parental exposure to arsenic and 17 metals and risk of neural tube defects (myelomeningocele and meningocele) in a case control study in Bangladesh. METHODS: Exposure assessment included analysis of maternal and paternal toenail samples using inductively coupled plasma mass spectrometry (ICP-MS). A total of 278 participants (155 cases and 123 controls) with data collected from 2016 to 2020 were included in the analysis. RESULTS: In the paternal models, a one-unit increase in the natural logarithm of paternal toenail arsenic was associated with a 74% (odds ratio: 1.74, 95% confidence interval: 1.26-2.42) greater odds of having a child with spina bifida, after adjusting for relevant covariates. Additionally, paternal exposure to aluminum, cobalt, chromium, iron, selenium, and vanadium was associated with increased odds of having a child with spina bifida in the adjusted models. In the maternal models, a one-unit increase in the natural logarithm of maternal toenail selenium and zinc levels was related to a 382% greater (odds ratio: 4.82, 95% confidence interval: 1.32-17.60) and 89% lower (odds ratio: 0.11, 95% confidence interval: 0.03-0.42) odds of having a child with spina bifida in the adjusted models, respectively. Results did not suggest an interaction between parental toenail metals and maternal serum folate. DISCUSSION: Parental toenail levels of numerous metals were associated with increased risk of spina bifida in Bangladeshi infants. Paternal arsenic exposure was positively associated with neural tube defects in children and is of particular concern given the widespread arsenic poisoning of groundwater resources in Bangladesh and the lack of nutritional interventions aimed to mitigate paternal arsenic exposure. The findings add to the growing body of literature of the impact of metals, especially paternal environmental factors, on child health.


Assuntos
Arsênio , Disrafismo Espinal , Bangladesh/epidemiologia , Estudos de Casos e Controles , Humanos , Masculino , Fatores de Risco , Disrafismo Espinal/epidemiologia , Disrafismo Espinal/etiologia
7.
Clin Nutr ; 40(8): 4863-4870, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34358830

RESUMO

BACKGROUND & AIMS: Prospective and longitudinal data on the association between acylcarnitines and gestational diabetes (GDM) are lacking. This study aims to prospectively investigate 28 acylcarnitines in relation to subsequent GDM risk. METHODS: Within the NICHD Fetal Growth Studies-Singleton Cohort, plasma levels of acylcarnitines and cardiometabolic biomarkers were measured at gestational week (GW) 10-14, 15-26, 23-31, and 33-39 among 107 GDM cases and 214 controls. RESULTS: At GW 10-14, per standard deviation (SD) increased level of C14:1-OH was associated with a 55% increased risk of GDM after adjusting for major risk factors for GDM [OR (95% CI): 1.55 (1.05-2.29)]. At GW 15-26, C4, C8:1 and C16:1-OH were associated with an increased risk of GDM [OR (95% CI) for per SD increase: 1.42 (1.01-2.00), 1.41 (1.02-1.96), and 1.77 (1.10-2.84), respectively]. Whereas increased C10 and C18 were related to lower risk of GDM [OR (95% CI) for per SD increase: 0.74 (0.55-1.00), and 0.69 (0.49-0.97), respectively]. Moreover, we observed correlations of individual acylcarnitine with multiple clinical markers implicated in glucose homeostasis and cardiometabolic function among non-GDM women. CONCLUSIONS: Our results demonstrate that several plasma acylcarnitine species are differentially associated with GDM risk by chain length. Future studies are warranted to investigate the distinct roles of individual acylcarnitine in glucose homeostasis in pregnancy.

8.
Ophthalmol Sci ; 1(1)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34382031

RESUMO

Purpose: Large-scale genome-wide association studies (GWAS) have reported important single nucleotide polymorphisms (SNPs) with significant associations with age-related macular degeneration (AMD). However, their role in disease development remains elusive. This study aimed to assess SNP-metabolite associations (i.e., metabolite quantitative trait loci [met-QTL]) and to provide insights into the biological mechanisms of AMD risk SNPs. Design: Cross-sectional multicenter study (Boston, Massachusetts, and Coimbra, Portugal). Participants: Patients with AMD (n = 388) and control participants (n = 98) without any vitreoretinal disease (> 50 years). Methods: Age-related macular degeneration grading was performed using color fundus photographs according to the Age-Related Eye Disease Study classification scheme. Fasting blood samples were collected and evaluated with mass spectrometry for metabolomic profiling and Illumina OmniExpress for SNPs profiling. Analyses of met-QTL of endogenous metabolites were conducted using linear regression models adjusted for age, gender, smoking, 10 metabolite principal components (PCs), and 10 SNP PCs. Additionally, we analyzed the cumulative effect of AMD risk SNPs on plasma metabolites by generating genetic risk scores and assessing their associations with metabolites using linear regression models, accounting for the same covariates. Modeling was performed first for each cohort, and then combined by meta-analysis. Multiple comparisons were accounted for using the false discovery rate (FDR). Main Outcome Measures: Plasma metabolite levels associated with AMD risk SNPs. Results: After quality control, data for 544 plasma metabolites were included. Meta-analysis of data from all individuals (AMD patients and control participants) identified 28 significant met-QTL (ß = 0.016-0.083; FDR q-value < 1.14 × 10-2), which corresponded to 5 metabolites and 2 genes: ASPM and LIPC. Polymorphisms in the LIPC gene were associated with phosphatidylethanolamine metabolites, which are glycerophospholipids, and polymorphisms in the ASPM gene with branched-chain amino acids. Similar results were observed when considering only patients with AMD. Genetic risk score-metabolite associations further supported a global impact of AMD risk SNPs on the plasma metabolome. Conclusions: This study demonstrated that genomic-metabolomic associations can provide insights into the biological relevance of AMD risk SNPs. In particular, our results support that the LIPC gene and the glycerophospholipid metabolic pathway may play an important role in AMD, thus offering new potential therapeutic targets for this disease.

9.
J Bone Miner Metab ; 39(6): 1058-1065, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34392464

RESUMO

INTRODUCTION: Neutrophil gelatinase-associated lipocalin (NGAL) is not only a biomarker of kidney injury but also a bone-derived factor involved in metabolism. We aimed to explore relationships between plasma NGAL and chronic kidney disease-mineral bone disorder (CKD-MBD) parameters in maintenance hemodialysis (MHD) patients. MATERIALS AND METHODS: First, a cross sectional observational study, including 105 MHD patients, was conducted to explore relationships between plasma NGAL levels and CKD-MBD parameters. Second, impact of parathyroidectomy and auto-transplantation (PTX + AT) on plasma NGAL was investigated in 12 MHD patients with severe secondary hyperparathyroidism (SHPT). RESULTS: According to Spearman correlation analysis, plasma NGAL levels were positively correlated with female (r = 0.243, P = 0.012), vintage (r = 0.290, P = 0.003), Klotho (r = 0.234, P = 0.016), calcium(Ca) (r = 0.332, P = 0.001), alkaline phosphatase (ALP) (r = 0.401, P < 0.001) and intact parathyroid hormone (iPTH) (r = 0.256, P = 0.008); while inversely correlated with albumin(Alb) (r = - 0.201, P = 0.039). After adjusting for age, sex, vintage, Alb and all parameters of CKD-MBD(Ca, P, lg(ALP), lg(iPTH), Klotho and fibroblast growth factor 23(FGF23)), lg(NGAL) were positively correlated with Ca (r = 0.481, P < 0.001), P (r = 0.336, P = 0.037), lg(ALP) (r = 0.646, P < 0.001) in Partial correlation analysis; further multiple linear regression analysis showed same positive associations between lg(NGAL) and Ca (ß = 0.330, P = 0.002), P (ß = 0.218, P = 0.037), lg(ALP) (ß = 0.671, P < 0.001). During the 4-7 days after PTX + AT, plasma NGAL decreased from 715.84 (578.73, 988.14) to 688.42 (660.00, 760.26) ng/mL (P = 0.071), Klotho increased from 496.45 (341.73, 848.30) to 1138.25 (593.87, 2009.27) pg/mL (P = 0.099). CONCLUSION: Plasma NGAL levels were positively associated with ALP in MHD patients; and downtrends were shown after PTX + AT in patients with severe SHPT. These findings suggest that NGAL is a participant in CKD-MBD under MHD condition.

10.
Sci Total Environ ; 796: 148767, 2021 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-34273838

RESUMO

Studies have shown contact with nature has positive psychological, neurological, and cognitive benefits. Whether the built environment can affect genetic predisposition of Alzheimer's disease (AD) should be explored. We aimed to examine whether greenness around the residential environment can modify the effect of genetic AD risk on cognitive function. We used a genetic sub-study of the Chinese Longitudinal Healthy Longevity Survey including 1199 older adults (mean age: 100.3 ± 3.4 years) aged 90 years old or older. We used Polygenic Risk Score (PRS) to quantify the genetic AD risk and two types of measurements based on Normalized Difference Vegetation Index (NDVI) to access the residential greenness (contemporaneous and annual average NDVI). Contemporaneous NDVI values were the NDVI value collected at the corresponding survey, and the annual average NDVI was the average value of NDVI during the year before the corresponding survey. We defined cognitive impairment as having a Mini-Mental State Examination score below 25. In the multivariable logistics regression models, contemporaneous NDVI and genetic AD risk were associated with cognitive impairment. Among those with low genetic AD risk, the risk of cognitive impairment was lower in those living around higher greenness (contemporaneous NDVI OR: 0.55, 95% CI: [0.34, 0.86]; Pinteraction: 0.071; annual average NDVI OR: 0.49, 95% CI: [0.31, 0.79]; Pinteraction: 0.040). We did not observe significant associations between greenness and cognitive impairment among those with high genetic AD risk. Prevention efforts using PRS warrant a higher granularity of environmental exposures and biological etiology data.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Ambiente Construído , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Humanos , Estudos Longitudinais , Fatores de Risco
11.
Am J Clin Nutr ; 114(5): 1646-1654, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34291275

RESUMO

BACKGROUND: The tryptophan-kynurenine pathway is linked to inflammation. We hypothesize that metabolites implicated in this pathway may be associated with the risk of heart failure (HF) or atrial fibrillation (AF) in a population at high risk of cardiovascular disease. OBJECTIVES: We aimed to prospectively analyze the associations of kynurenine-related metabolites with the risk of HF and AF and to analyze a potential effect modification by the randomized interventions of the PREDIMED (Prevención con Dieta Mediterránea) trial with Mediterranean diet (MedDiet). METHODS: Two case-control studies nested within the PREDIMED trial were designed. We selected 324 incident HF cases and 502 incident AF cases individually matched with ≤3 controls. Conditional logistic regression models were fitted. Interactions with the intervention were tested for each of the baseline plasma metabolites measured by LC-tandem MS. RESULTS: Higher baseline kynurenine:tryptophan ratio (OR for 1 SD: 1.20; 95% CI: 1.01, 1.43) and higher levels of kynurenic acid (OR: 1.19; 95% CI: 1.01, 1.40) were associated with HF. Quinolinic acid was associated with AF (OR: 1.15; 95% CI: 1.01, 1.32) and HF (OR: 1.25; 95% CI: 1.04, 1.49). The MedDiet intervention modified the positive associations of kynurenine (Pinteraction = 0.006), kynurenic acid (Pinteraction = 0.008), and quinolinic acid (Pinteraction = 0.033) with HF and the association between kynurenic acid and AF (Pinteraction = 0.02). CONCLUSIONS: We found that tryptophan-kynurenine pathway metabolites were prospectively associated with higher HF risk and to a lesser extent with AF risk. Moreover, an effect modification by MedDiet was observed for the association between plasma baseline kynurenine-related metabolites and the risk of HF, showing that the positive association of increased levels of these metabolites and HF was restricted to the control group.

12.
Front Med (Lausanne) ; 8: 678047, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34295910

RESUMO

Clinicians handle a growing amount of clinical, biometric, and biomarker data. In this "big data" era, there is an emerging faith that the answer to all clinical and scientific questions reside in "big data" and that data will transform medicine into precision medicine. However, data by themselves are useless. It is the algorithms encoding causal reasoning and domain (e.g., clinical and biological) knowledge that prove transformative. The recent introduction of (health) data science presents an opportunity to re-think this data-centric view. For example, while precision medicine seeks to provide the right prevention and treatment strategy to the right patients at the right time, its realization cannot be achieved by algorithms that operate exclusively in data-driven prediction modes, as do most machine learning algorithms. Better understanding of data science and its tasks is vital to interpret findings and translate new discoveries into clinical practice. In this review, we first discuss the principles and major tasks of data science by organizing it into three defining tasks: (1) association and prediction, (2) intervention, and (3) counterfactual causal inference. Second, we review commonly-used data science tools with examples in the medical literature. Lastly, we outline current challenges and future directions in the fields of medicine, elaborating on how data science can enhance clinical effectiveness and inform medical practice. As machine learning algorithms become ubiquitous tools to handle quantitatively "big data," their integration with causal reasoning and domain knowledge is instrumental to qualitatively transform medicine, which will, in turn, improve health outcomes of patients.

13.
Artigo em Inglês | MEDLINE | ID: mdl-34119532

RESUMO

BACKGROUND: Infants with bronchiolitis are at increased risk for developing asthma. Growing evidence suggests bronchiolitis is a heterogeneous condition. OBJECTIVES: We sought to identify biologically distinct subgroups based on the metabolome signatures (metabotypes) in infants with severe bronchiolitis and to examine the longitudinal relationships of metabotypes with asthma development. METHODS: In a multicenter prospective cohort study of infants (age, <12 months) hospitalized for bronchiolitis, the nasopharyngeal airway metabolome was profiled at hospitalization. Using a clustering approach, this study identified mutually exclusive metabotypes. This study also examined their longitudinal association with the risk of developing asthma by 5 years of age. RESULTS: Of 918 infants hospitalized for bronchiolitis (median age, 3 months), this study identified 5 distinct metabotypes-characterized by their nasopharyngeal metabolome profile: A, glycerophosphocholine-high; B, amino acid-high, polyunsaturated fatty acid-low; C, amino acid-high, glycerophospholipid-low; D, glycerophospholipid-high; and E, mixed. Compared with infants with metabotype A (who clinically resembled "classic" bronchiolitis), infants with metabotype B had a significantly higher risk for developing asthma (23% vs 41%; adjusted odds ratio, 2.22; 95% CI, 1.07-4.69). The pathway analysis showed that metabotype B had enriched amino acid (eg, methionine, histidine, glutathione) and α-linolenic/linoleic acid metabolism pathways (false discovery rate, <5 × 10-14 for all). Finally, the transcriptome analysis revealed that infants with metabotype B had upregulated IFN-α and IL-6/JAK/STAT3 pathways and downregulated fatty acid metabolism pathways (false discovery rate, <0.05 for both). CONCLUSIONS: In this multicenter prospective cohort study of infants with severe bronchiolitis, the clustering analysis of metabolome data identified biologically distinct metabotypes, including a metabotype characterized by high inflammatory amino acids and low polyunsaturated fatty acids that is at significantly increased risk for developing asthma.

14.
Sci Rep ; 11(1): 12453, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127738

RESUMO

Lung cancer is the most frequent cause of cancer death worldwide. It affects more men than women, and men generally have worse survival outcomes. We compared gene co-expression networks in affected and unaffected lung tissue from 126 consecutive patients with Stage IA-IV lung cancer undergoing surgery with curative intent. We observed marked degradation of a sex-associated transcription network in tumour tissue. This disturbance, detected in 27.7% of male tumours in the discovery dataset and 27.3% of male tumours in a further 123-sample replication dataset, was coincident with partial losses of the Y chromosome and extensive autosomal DNA hypomethylation. Central to this network was the epigenetic modifier and regulator of sexually dimorphic gene expression, KDM5D. After accounting for prognostic and epidemiological covariates including stage and histology, male patients with tumour KDM5D deficiency showed a significantly increased risk of death (Hazard Ratio [HR] 3.80, 95% CI 1.40-10.3, P = 0.009). KDM5D deficiency was confirmed as a negative prognostic indicator in a further 1100 male lung tumours (HR 1.67, 95% CI 1.4-2.0, P = 1.2 × 10-10). Our findings identify tumour deficiency of KDM5D as a prognostic marker and credible mechanism underlying sex disparity in lung cancer.


Assuntos
Biomarcadores Tumorais/genética , Deleção Cromossômica , Cromossomos Humanos Y/genética , Histona Desmetilases/genética , Neoplasias Pulmonares/genética , Antígenos de Histocompatibilidade Menor/genética , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Metilação de DNA , Conjuntos de Dados como Assunto , Epigênese Genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Disparidades nos Níveis de Saúde , Histona Desmetilases/deficiência , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pneumonectomia , Prognóstico , Medição de Risco/estatística & dados numéricos , Fatores Sexuais , Sequenciamento Completo do Exoma
15.
Metabolites ; 11(5)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064960

RESUMO

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case-control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR for 1 SD increase: 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies.

17.
Front Med (Lausanne) ; 8: 665057, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33912579

RESUMO

Purpose: Emerging evidence suggests a potential role of interleukin-6 pathways-trans-signaling with soluble interleukin-6 receptors-in the asthma pathobiology. Despite the evidence for their associations with asthma, the causal role of soluble interleukin-6 receptors remains uncertain. We investigated the relations of soluble interleukin-6 receptors with asthma and its major phenotypes. Methods: We conducted a two-sample Mendelian randomization study. As genetic instruments, we selected 33 independent cis-acting variants strongly associated with the level of plasma soluble interleukin-6 receptor in the INTERVAL study. To investigate the association of variants with asthma and its phenotypes, we used genome-wide association study data from the UK Biobank. We combined variant-specific causal estimates by the inverse-variance weighted method for each outcome. Results: Genetically-instrumented soluble interleukin-6 receptor level was associated with a significantly higher risk of overall asthma (OR per one standard deviation increment in inverse-rank normalized soluble interleukin-6 receptor level, 1.02; 95%CI, 1.01-1.03; P = 0.004). Sensitivity analyses demonstrated consistent results and indicated no directional pleiotropy-e.g., MR-Egger (OR, 1.03; 95%CI, 1.01-1.05; P = 0.002; P intercept =0.37). In the stratified analysis, the significant association persisted across asthma phenotypes-e.g., childhood asthma (OR, 1.05; 95%CI, 1.02-1.08; P < 0.001) and obese asthma (OR, 1.02; 95%CI 1.01-1.03; P = 0.007). Sensitivity analysis using 16 variants selected with different thresholds also demonstrated significant associations with overall asthma and its phenotypes. Conclusion: Genetically-instrumented soluble interleukin-6 receptor level was causally associated with modestly but significantly higher risks of asthma and its phenotypes. Our observations support further investigations into identifying specific endotypes in which interleukin-6 pathways may play major roles.

18.
Am J Clin Nutr ; 114(1): 238-247, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33829245

RESUMO

BACKGROUND: Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk. OBJECTIVES: This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk. METHODS: A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs. RESULTS: A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant. CONCLUSIONS: Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk.


Assuntos
4-Butirolactona/análogos & derivados , Doença das Coronárias/patologia , Microbioma Gastrointestinal , Lignanas/metabolismo , Metilaminas/metabolismo , 4-Butirolactona/metabolismo , Adulto , Estudos de Casos e Controles , Dieta/normas , Feminino , Humanos , Masculino , Estudos Prospectivos , Fatores de Risco , Estados Unidos
19.
J Cosmet Dermatol ; 20(10): 3205-3212, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33825341

RESUMO

BACKGROUND: The incidence of hyaluronic acid (HA) embolism has increased markedly in recent years. HA embolism can lead to serious complications such as blindness, eye and eyelid movement disorders, skin necrosis, and cerebral embolism. However, there is a lack of robust clinical evidence regarding the benefits of treatment of HA embolism with intra-arterial thrombolytic therapy (IATT). METHODS: In the present study, we enrolled 45 patients with decreased visual acuity, including 40 patients with symptoms of vision loss and eight patients with symptoms of intracranial embolism. The patients underwent emergency IATT via hyaluronidase and papaverine injections, followed by conventional sequential therapy. RESULTS: In the 45 patients with symptoms of vision loss, 16 (36%) exhibited improvements in final visual acuity, even when the clinical application of the thrombolytic treatments was performed beyond the recommended window for optimal treatment. The facial skin necrosis of all patients was restored to near normal appearance. Notably, for eight patients with suspected symptoms of intracranial infarction we performed cerebral angiography and IATT, and in two patients obtained partial recanalization of the obstruction, the symptoms of heavy headache and binocular distension pain were improved in one patient with intracranial embolism after IATT treatment. CONCLUSION: Our results indicate that IATT is feasible for patients with vision loss induced by HA embolism. IATT combined with conventional sequential therapy was beneficial in the recovery from other serious HA embolism complications. Nevertheless, the underlying pathophysiological mechanism needs to be clarified in future animal experiments.


Assuntos
Preenchedores Dérmicos , Ácido Hialurônico , Animais , Cegueira/induzido quimicamente , Preenchedores Dérmicos/efeitos adversos , Humanos , Ácido Hialurônico/efeitos adversos , Hialuronoglucosaminidase/uso terapêutico , Terapia Trombolítica
20.
Metabolites ; 11(3)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801085

RESUMO

The purpose of this study was to analyze the association between plasma metabolite levels and dark adaptation (DA) in age-related macular degeneration (AMD). This was a cross-sectional study including patients with AMD (early, intermediate, and late) and control subjects older than 50 years without any vitreoretinal disease. Fasting blood samples were collected and used for metabolomic profiling with ultra-performance liquid chromatography-mass spectrometry (LC-MS). Patients were also tested with the AdaptDx (MacuLogix, Middletown, PA, USA) DA extended protocol (20 min). Two measures of dark adaptation were calculated and used: rod-intercept time (RIT) and area under the dark adaptation curve (AUDAC). Associations between dark adaption and metabolite levels were tested using multilevel mixed-effects linear modelling, adjusting for age, gender, body mass index (BMI), smoking, race, AMD stage, and Age-Related Eye Disease Study (AREDS) formulation supplementation. We included a total of 71 subjects: 53 with AMD (13 early AMD, 31 intermediate AMD, and 9 late AMD) and 18 controls. Our results revealed that fatty acid-related lipids and amino acids related to glutamate and leucine, isoleucine and valine metabolism were associated with RIT (p < 0.01). Similar results were found when AUDAC was used as the outcome. Fatty acid-related lipids and amino acids are associated with DA, thus suggesting that oxidative stress and mitochondrial dysfunction likely play a role in AMD and visual impairment in this condition.

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