Publications by authors named "Ioanna Tzoulaki"

170 Publications

Adherence to Mediterranean Diet and Cognitive Abilities in the Greek Cohort of Epirus Health Study.

Nutrients 2021 Sep 25;13(10). Epub 2021 Sep 25.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece.

The Mediterranean diet is commonly proposed as a major modifiable protective factor that may delay cognitive impairment in the elderly. The aim of the study was to investigate the cross-sectional association of adherence to the Mediterranean diet with cognitive abilities in a younger Greek population. A total of 1201 healthy adults aged 21-77 years (mean: 47.8) from the Epirus Health Study cohort were included in the analysis. Adherence to the Mediterranean diet was measured using the 14-point Mediterranean Diet Adherence Screener (MEDAS) and cognition was measured using the Trail Making Test, the Verbal Fluency test and the Logical Memory test. Statistical analysis was performed using multiple linear regression models adjusted for age, sex, education, body mass index, smoking status, alcohol consumption and physical activity. Overall, no association was found between the MEDAS score and cognitive tests, which could be explained by the young mean age and high level of education of the participants. Future studies should target young and middle-aged individuals to gain further understanding of the association between Mediterranean diet and cognition in this age group.
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http://dx.doi.org/10.3390/nu13103363DOI Listing
September 2021

Prevalence and Determinants of Sex-Specific Dietary Supplement Use in a Greek Cohort.

Nutrients 2021 Aug 20;13(8). Epub 2021 Aug 20.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, 45110 Ioannina, Greece.

We describe the profile of dietary supplement use and its correlates in the Epirus Health Study cohort, which consists of 1237 adults (60.5% women) residing in urban north-west Greece. The association between dietary supplement use and demographic characteristics, lifestyle behaviors, personal medical history and clinical measurements was assessed using logistic regression models, separately for women and men. The overall prevalence of dietary supplement use was 31.4%, and it was higher in women (37.3%) compared to men (22.4%; -value = 4.2). Based on multivariable logistic regression models, dietary supplement use in women was associated with age (positively until middle-age and slightly negatively afterwards), the presence of a chronic health condition (OR = 1.71; 95% CI, 1.18-2.46), lost/removed teeth (OR = 0.52; 95% CI, 0.35-0.78) and diastolic blood pressure (OR per 5 mmHg increase =0.84; 95% CI, 0.73-0.96); body mass index and worse general health status were borderline inversely associated. In men, dietary supplement use was positively associated with being employed (OR = 2.53; 95% CI, 1.21-5.29). A considerable proportion of our sample used dietary supplements, and the associated factors differed between women and men.
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http://dx.doi.org/10.3390/nu13082857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399686PMC
August 2021

Exposure to pesticides and childhood leukemia risk: A systematic review and meta-analysis.

Environ Pollut 2021 Sep 18;285:117376. Epub 2021 May 18.

Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, 45110, Greece; Center for Evidence Synthesis in Health, Brown University School of Public Health, Providence, RI, USA; Institute of Biosciences, University Research Center of Loannina, University of Ioannina, Ioannina, Greece. Electronic address:

Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15-3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39-4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00-1.99) and insecticide (OR: 1.60, 95%CI: 1.11-2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12-0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44-3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98-5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (OR: 1.75, 95%CI: 1.08-2.85; OR: 1.20, 95%CI: 1.07-1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure.
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http://dx.doi.org/10.1016/j.envpol.2021.117376DOI Listing
September 2021

Validity of observational evidence on putative risk and protective factors: appraisal of 3744 meta-analyses on 57 topics.

BMC Med 2021 07 6;19(1):157. Epub 2021 Jul 6.

Meta-Research Innovation Center at Stanford (METRICS), Stanford, CA, 94305, USA.

Background: The validity of observational studies and their meta-analyses is contested. Here, we aimed to appraise thousands of meta-analyses of observational studies using a pre-specified set of quantitative criteria that assess the significance, amount, consistency, and bias of the evidence. We also aimed to compare results from meta-analyses of observational studies against meta-analyses of randomized controlled trials (RCTs) and Mendelian randomization (MR) studies.

Methods: We retrieved from PubMed (last update, November 19, 2020) umbrella reviews including meta-analyses of observational studies assessing putative risk or protective factors, regardless of the nature of the exposure and health outcome. We extracted information on 7 quantitative criteria that reflect the level of statistical support, the amount of data, the consistency across different studies, and hints pointing to potential bias. These criteria were level of statistical significance (pre-categorized according to 10, 0.001, and 0.05 p-value thresholds), sample size, statistical significance for the largest study, 95% prediction intervals, between-study heterogeneity, and the results of tests for small study effects and for excess significance.

Results: 3744 associations (in 57 umbrella reviews) assessed by a median number of 7 (interquartile range 4 to 11) observational studies were eligible. Most associations were statistically significant at P < 0.05 (61.1%, 2289/3744). Only 2.6% of associations had P < 10, ≥1000 cases (or ≥20,000 participants for continuous factors), P < 0.05 in the largest study, 95% prediction interval excluding the null, and no large between-study heterogeneity, small study effects, or excess significance. Across the 57 topics, large heterogeneity was observed in the proportion of associations fulfilling various quantitative criteria. The quantitative criteria were mostly independent from one another. Across 62 associations assessed in both RCTs and in observational studies, 37.1% had effect estimates in opposite directions and 43.5% had effect estimates differing beyond chance in the two designs. Across 94 comparisons assessed in both MR and observational studies, such discrepancies occurred in 30.8% and 54.7%, respectively.

Conclusions: Acknowledging that no gold-standard exists to judge whether an observational association is genuine, statistically significant results are common in observational studies, but they are rarely convincing or corroborated by randomized evidence.
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http://dx.doi.org/10.1186/s12916-021-02020-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259334PMC
July 2021

Prognostic factors for adverse outcomes in patients with COVID-19: a field-wide systematic review and meta-analysis.

Eur Respir J 2021 Jun 25. Epub 2021 Jun 25.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.

Introduction: The individual prognostic factors for COVID-19 are unclear. For this reason, we aimed to present a state-of-the-art systematic review and meta-analysis on the prognostic factors for adverse outcomes in COVID-19 patients.

Methods: We systematically reviewed PubMed from January 1, 2020 to July 26, 2020 to identify non-overlapping studies examining the association of any prognostic factor with any adverse outcome in patients with COVID-19. Random-effects meta-analysis was performed, and between-study heterogeneity was quantified using I metric. Presence of small-study effects was assessed by applying the Egger's regression test.

Results: We identified 428 eligible articles, which were used in a total of 263 meta-analyses examining the association of 91 unique prognostic factors with 11 outcomes. Angiotensin-converting enzyme inhibitors, obstructive sleep apnea, pharyngalgia, history of venous thromboembolism, sex, coronary heart disease, cancer, chronic liver disease, chronic obstructive pulmonary disease, dementia, any immunosuppressive medication, peripheral arterial disease, rheumatological disease and smoking were associated with at least one outcome and had >1000 events, p-value <0.005, I <50%, 95% prediction interval excluding the null value, and absence of small-study effects in the respective meta-analysis. The risk of bias assessment using the Quality In Prognosis Studies tool indicated high risk of bias in 302 of 428 articles for study participation, 389 articles for adjustment for other prognostic factors, and 396 articles for statistical analysis and reporting.

Conclusions: Our findings could be used for prognostic model building and guide patients' selection for randomised clinical trials.
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http://dx.doi.org/10.1183/13993003.02964-2020DOI Listing
June 2021

Awareness, knowledge and trust in the Greek authorities towards COVID-19 pandemic: results from the Epirus Health Study cohort.

BMC Public Health 2021 06 12;21(1):1125. Epub 2021 Jun 12.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

Background: To assess the level of knowledge and trust in the policy decisions taken regarding the coronavirus disease (COVID-19) pandemic among Epirus Health Study (EHS) participants.

Methods: The EHS is an ongoing and deeply-phenotyped prospective cohort study that has recruited 667 participants in northwest Greece until August 31st, 2020. Level of knowledge on coronavirus (SARS-CoV-2) transmission and COVID-19 severity was labeled as poor, moderate or good. Variables assessing knowledge and beliefs towards the pandemic were summarized overall and by sex, age group (25-39, 40-49, 50-59, ≥60 years) and period of report (before the lifting of lockdown measures in Greece: March 30th to May 3rd, and two post-lockdown time periods: May 4th to June 31st, July 1st to August 31st). A hypothesis generating exposure-wide association analysis was conducted to evaluate the associations between 153 agnostically-selected explanatory variables and participants' knowledge. Correction for multiple comparisons was applied using a false discovery rate (FDR) threshold of 5%.

Results: A total of 563 participants (49 years mean age; 60% women) had available information on the standard EHS questionnaire, the clinical and biochemical measurements, and the COVID-19-related questionnaire. Percentages of poor, moderate and good knowledge status regarding COVID-19 were 4.5, 10.0 and 85.6%, respectively. The majority of participants showed absolute or moderate trust in the Greek health authorities for the management of the epidemic (90.1%), as well as in the Greek Government (84.7%) and the official national sources of information (87.4%). Trust in the authorities was weaker in younger participants and those who joined the study after the lifting of lockdown measures (p-value≤0.001). None of the factors examined was associated with participants' level of knowledge after correction for multiple testing.

Conclusions: High level of knowledge about the COVID-19 pandemic and trust in the Greek authorities was observed, possibly due to the plethora of good quality publicly available information and the timely management of the pandemic at its early stages in Greece. Information campaigns for the COVID-19 pandemic should be encouraged even after the lifting of lockdown measures to increase public awareness.
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http://dx.doi.org/10.1186/s12889-021-11193-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196287PMC
June 2021

Glycemic Control, Diabetic Complications, and Risk of Dementia in Patients With Diabetes: Results From a Large U.K. Cohort Study.

Diabetes Care 2021 May 25. Epub 2021 May 25.

Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, U.K.

Objective: Type 2 diabetes is an established risk factor for dementia. However, the roles of glycemic control and diabetic complications in the development of dementia have been less well substantiated. This large-scale cohort study aims to examine associations of longitudinal HbA levels and diabetic complications with the risk of dementia incidence among patients with type 2 diabetes.

Research Design And Methods: Data of eligible patients with diabetes, aged ≥50 years in the U.K. Clinical Practice Research Datalink from 1987 to 2018, were analyzed. Time-varying Cox regressions were used to estimate adjusted hazard ratios (HRs) and 95% CIs for dementia risk.

Results: Among 457,902 patients with diabetes, 28,627 (6.3%) incident dementia cases were observed during a median of 6 years' follow-up. Patients with recorded hypoglycemic events or microvascular complications were at higher risk of dementia incidence compared with those without such complications (HR 1.30 [95% CI 1.22-1.39] and 1.10 [1.06-1.14], respectively). The HbA level, modeled as a time-varying exposure, was associated with increased dementia risk (HR 1.08 [95% CI 1.07-1.09] per 1% HbA increment) among 372,287 patients with diabetes with postdiagnosis HbA records. Similarly, a higher coefficient of variation of HbA during the initial 3 years of follow-up was associated with higher subsequent dementia risk (HR 1.03 [95% CI 1.01-1.04] per 1-SD increment).

Conclusions: Higher or unstable HbA levels and the presence of diabetic complications in patients with type 2 diabetes are associated with increased dementia risk. Effective management of glycemia might have a significant role in maintaining cognitive health among older adults with diabetes.
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http://dx.doi.org/10.2337/dc20-2850DOI Listing
May 2021

Associations of circulating choline and its related metabolites with cardiometabolic biomarkers: an international pooled analysis.

Am J Clin Nutr 2021 09;114(3):893-906

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Choline is an essential nutrient; however, the associations of choline and its related metabolites with cardiometabolic risk remain unclear.

Objective: We examined the associations of circulating choline, betaine, carnitine, and dimethylglycine (DMG) with cardiometabolic biomarkers and their potential dietary and nondietary determinants.

Methods: The cross-sectional analyses included 32,853 participants from 17 studies, who were free of cancer, cardiovascular diseases, chronic kidney diseases, and inflammatory bowel disease. In each study, metabolites and biomarkers were log-transformed and standardized by means and SDs, and linear regression coefficients (β) and 95% CIs were estimated with adjustments for potential confounders. Study-specific results were combined by random-effects meta-analyses. A false discovery rate <0.05 was considered significant.

Results: We observed moderate positive associations of circulating choline, carnitine, and DMG with creatinine [β (95% CI): 0.136 (0.084, 0.188), 0.106 (0.045, 0.168), and 0.128 (0.087, 0.169), respectively, for each SD increase in biomarkers on the log scale], carnitine with triglycerides (β = 0.076; 95% CI: 0.042, 0.109), homocysteine (β = 0.064; 95% CI: 0.033, 0.095), and LDL cholesterol (β = 0.055; 95% CI: 0.013, 0.096), DMG with homocysteine (β = 0.068; 95% CI: 0.023, 0.114), insulin (β = 0.068; 95% CI: 0.043, 0.093), and IL-6 (β = 0.060; 95% CI: 0.027, 0.094), but moderate inverse associations of betaine with triglycerides (β = -0.146; 95% CI: -0.188, -0.104), insulin (β = -0.106; 95% CI: -0.130, -0.082), homocysteine (β = -0.097; 95% CI: -0.149, -0.045), and total cholesterol (β = -0.074; 95% CI: -0.102, -0.047). In the whole pooled population, no dietary factor was associated with circulating choline; red meat intake was associated with circulating carnitine [β = 0.092 (0.042, 0.142) for a 1 serving/d increase], whereas plant protein was associated with circulating betaine [β = 0.249 (0.110, 0.388) for a 5% energy increase]. Demographics, lifestyle, and metabolic disease history showed differential associations with these metabolites.

Conclusions: Circulating choline, carnitine, and DMG were associated with unfavorable cardiometabolic risk profiles, whereas circulating betaine was associated with a favorable cardiometabolic risk profile. Future prospective studies are needed to examine the associations of these metabolites with incident cardiovascular events.
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http://dx.doi.org/10.1093/ajcn/nqab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408854PMC
September 2021

Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Nat Commun 2021 05 10;12(1):2579. Epub 2021 May 10.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.
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http://dx.doi.org/10.1038/s41467-021-22338-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110798PMC
May 2021

A Prospective Diet-Wide Association Study for Risk of Colorectal Cancer in EPIC.

Clin Gastroenterol Hepatol 2021 Apr 24. Epub 2021 Apr 24.

Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.

Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk.

Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci.

Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04-1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02-1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04-1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93-0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90-0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90-0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92-0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94-0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93-0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons.

Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.
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http://dx.doi.org/10.1016/j.cgh.2021.04.028DOI Listing
April 2021

Circulating trimethylamine N-oxide in association with diet and cardiometabolic biomarkers: an international pooled analysis.

Am J Clin Nutr 2021 05;113(5):1145-1156

Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Trimethylamine N-oxide (TMAO), a diet-derived, gut microbial-host cometabolite, has been linked to cardiometabolic diseases. However, the relations remain unclear between diet, TMAO, and cardiometabolic health in general populations from different regions and ethnicities.

Objectives: To examine associations of circulating TMAO with dietary and cardiometabolic factors in a pooled analysis of 16 population-based studies from the United States, Europe, and Asia.

Methods: Included were 32,166 adults (16,269 white, 13,293 Asian, 1247 Hispanic/Latino, 1236 black, and 121 others) without cardiovascular disease, cancer, chronic kidney disease, or inflammatory bowel disease. Linear regression coefficients (β) were computed for standardized TMAO with harmonized variables. Study-specific results were combined by random-effects meta-analysis. A false discovery rate <0.10 was considered significant.

Results: After adjustment for potential confounders, circulating TMAO was associated with intakes of animal protein and saturated fat (β = 0.124 and 0.058, respectively, for a 5% energy increase) and with shellfish, total fish, eggs, and red meat (β = 0.370, 0.151, 0.081, and 0.056, respectively, for a 1 serving/d increase). Plant protein and nuts showed inverse associations (β = -0.126 for a 5% energy increase from plant protein and -0.123 for a 1 serving/d increase of nuts). Although the animal protein-TMAO association was consistent across populations, fish and shellfish associations were stronger in Asians (β = 0.285 and 0.578), and egg and red meat associations were more prominent in Americans (β = 0.153 and 0.093). Besides, circulating TMAO was positively associated with creatinine (β = 0.131 SD increase in log-TMAO), homocysteine (β = 0.065), insulin (β = 0.048), glycated hemoglobin (β = 0.048), and glucose (β = 0.023), whereas it was inversely associated with HDL cholesterol (β = -0.047) and blood pressure (β = -0.030). Each TMAO-biomarker association remained significant after further adjusting for creatinine and was robust in subgroup/sensitivity analyses.

Conclusions: In an international, consortium-based study, animal protein was consistently associated with increased circulating TMAO, whereas TMAO associations with fish, shellfish, eggs, and red meat varied among populations. The adverse associations of TMAO with certain cardiometabolic biomarkers, independent of renal function, warrant further investigation.
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http://dx.doi.org/10.1093/ajcn/nqaa430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106754PMC
May 2021

Metformin and health outcomes: An umbrella review of systematic reviews with meta-analyses.

Eur J Clin Invest 2021 Jul 16;51(7):e13536. Epub 2021 Mar 16.

Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy.

Background: The objective was to capture the breadth of outcomes that have been associated with metformin use and to systematically assess the quality, strength and credibility of these associations using the umbrella review methodology.

Methods: Four major databases were searched until 31 May 2020. Meta-analyses of observational studies and meta-analyses of randomized controlled trials (RCTs) (including active and placebo control arms) were included.

Results: From 175 eligible publications, we identified 427 different meta-analyses, including 167 meta-analyses of observational studies, 147 meta-analyses of RCTs for metformin vs placebo/no treatment and 113 meta-analyses of RCTs for metformin vs active medications. There was no association classified as convincing or highly suggestive from meta-analyses of observational studies, but some suggestive/weak associations of metformin use with a lower mortality risk of CVD and cancer. In meta-analyses of RCTs, metformin was associated with a lower incidence of diabetes in people with prediabetes or no diabetes at baseline; lower ovarian hyperstimulation syndrome incidence (in women in controlled ovarian stimulation); higher success for clinical pregnancy rate in poly-cystic ovary syndrome (PCOS); and significant reduction in body mass index in people with type 1 diabetes mellitus, in women who have obesity/overweight with PCOS and in obese/overweight women. Of 175 publications, 166 scored as low or critically low quality per AMSTAR 2 criteria.

Conclusions: Observational evidence on metformin seems largely unreliable. Randomized evidence shows benefits for preventing diabetes and in some gynaecological and obstetrical settings. However, almost all meta-analyses are of low or critically low quality according to AMSTAR 2 criteria.
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http://dx.doi.org/10.1111/eci.13536DOI Listing
July 2021

Incidence of mild cognitive impairment in the elderly population in Greece: results from the HELIAD study.

Aging Clin Exp Res 2021 Oct 8;33(10):2679-2688. Epub 2021 Mar 8.

1st Department of Neurology, Aeginition University Hospital, National and Kapodistrian University of Athens Medical School, 72 Vassilissis Sophias Avenue, 11528, Athens, Greece.

Background: There are no published data on Mild Cognitive Impairment (MCI) incidence in people over 65 years of age in Greece, relevant literature is scarce for Southern Europe, and reported rates worldwide show great variability.

Aims: To investigate the incidence and risk factors of MCI and its subtypes in the elderly population in Greece.

Methods: The incidence cohort of the HELIAD study (Hellenic Epidemiological Longitudinal Investigation of Aging and Diet) comprised 955 individuals who received full neurological and neuropsychological evaluation on two separate occasions about three years apart.

Results: The MCI incidence rate in our cohort is 54.07 new cases per 1000 person-years, standardized by age and sex to 59.99. Each additional year of age over 65 raises the probability of novel MCI by 6.2%, while lower educational attainment more than doubles the risk for incident MCI. Apolipoprotein E-ε4 (APOE-ε4) carriage results in increased risk for MCI by more than 1.7 times. Incidence rates for amnestic MCI are slightly higher than for the non-amnestic subtype, and AD is the most common potential underlying etiology.

Discussion: The MCI incidence rate in the Greek population over 65 years of age is 54/1000 person-years. Advanced age and APOE-ε4 carriage are predisposing factors, while higher educational attainment was found to exert a protective effect.

Conclusions: MCI incidence in people over 65 years-old in Greece is consistent with reported rates around the world. Larger studies encompassing neuroimaging and cerebrospinal fluid biomarkers will hopefully shed more light on MCI epidemiology in Greece in the future.
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http://dx.doi.org/10.1007/s40520-021-01819-wDOI Listing
October 2021

Metabolic phenotyping and cardiovascular disease: an overview of evidence from epidemiological settings.

Heart 2021 Jul 19;107(14):1123-1129. Epub 2021 Feb 19.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK

Metabolomics, the comprehensive measurement of low-molecular-weight molecules in biological fluids used for metabolic phenotyping, has emerged as a promising tool to better understand pathways underlying cardiovascular disease (CVD) and to improve cardiovascular risk stratification. Here, we present the main methodologies for metabolic phenotyping, the methodological steps to analyse these data in epidemiological settings and the associated challenges. We discuss evidence from epidemiological studies linking metabolites to coronary heart disease and stroke. These studies indicate the systemic nature of CVD and identify associated metabolic pathways such as gut microbial cometabolism, branched-chain amino acids, glycerophospholipid and cholesterol metabolism, as well as activation of inflammatory processes. Integration of metabolomic with genomic data can provide new evidence for involved biochemical pathways and potential for causality using Mendelian randomisation. The clinical utility of metabolic biomarkers for cardiovascular risk stratification in healthy individuals has not yet been established. As sample sizes with high-dimensional molecular data increase in epidemiological settings, integration of metabolomic data across studies and platforms with other molecular data will lead to new understanding of the metabolic processes underlying CVD and contribute to identification of potentially novel preventive and pharmacological targets. Metabolic phenotyping offers a powerful tool in the characterisation of the molecular signatures of CVD, paving the way to new mechanistic understanding and therapies, as well as improving risk prediction of CVD patients. However, there are still challenges to face in order to contribute to clinically important improvements in CVD.
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http://dx.doi.org/10.1136/heartjnl-2019-315615DOI Listing
July 2021

COVID-19 mortality in the UK Biobank cohort: revisiting and evaluating risk factors.

Eur J Epidemiol 2021 Mar 15;36(3):299-309. Epub 2021 Feb 15.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Hospital, Norfolk Place, London, W21PG, UK.

Most studies of severe/fatal COVID-19 risk have used routine/hospitalisation data without detailed pre-morbid characterisation. Using the community-based UK Biobank cohort, we investigate risk factors for COVID-19 mortality in comparison with non-COVID-19 mortality. We investigated demographic, social (education, income, housing, employment), lifestyle (smoking, drinking, body mass index), biological (lipids, cystatin C, vitamin D), medical (comorbidities, medications) and environmental (air pollution) data from UK Biobank (N = 473,550) in relation to 459 COVID-19 and 2626 non-COVID-19 deaths to 21 September 2020. We used univariate, multivariable and penalised regression models. Age (OR = 2.76 [2.18-3.49] per S.D. [8.1 years], p = 2.6 × 10), male sex (OR = 1.47 [1.26-1.73], p = 1.3 × 10) and Black versus White ethnicity (OR = 1.21 [1.12-1.29], p = 3.0 × 10) were independently associated with and jointly explanatory of (area under receiver operating characteristic curve, AUC = 0.79) increased risk of COVID-19 mortality. In multivariable regression, alongside demographic covariates, being a healthcare worker, current smoker, having cardiovascular disease, hypertension, diabetes, autoimmune disease, and oral steroid use at enrolment were independently associated with COVID-19 mortality. Penalised regression models selected income, cardiovascular disease, hypertension, diabetes, cystatin C, and oral steroid use as jointly contributing to COVID-19 mortality risk; Black ethnicity, hypertension and oral steroid use contributed to COVID-19 but not non-COVID-19 mortality. Age, male sex and Black ethnicity, as well as comorbidities and oral steroid use at enrolment were associated with increased risk of COVID-19 death. Our results suggest that previously reported associations of COVID-19 mortality with body mass index, low vitamin D, air pollutants, renin-angiotensin-aldosterone system inhibitors may be explained by the aforementioned factors.
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http://dx.doi.org/10.1007/s10654-021-00722-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882869PMC
March 2021

Comparisons of Polyexposure, Polygenic, and Clinical Risk Scores in Risk Prediction of Type 2 Diabetes.

Diabetes Care 2021 04 9;44(4):935-943. Epub 2021 Feb 9.

Department of Biomedical Informatics, Harvard Medical School, Boston, MA

Objective: To establish a polyexposure score (PXS) for type 2 diabetes (T2D) incorporating 12 nongenetic exposures and examine whether a PXS and/or a polygenic risk score (PGS) improves diabetes prediction beyond traditional clinical risk factors.

Research Design And Methods: We identified 356,621 unrelated individuals from the UK Biobank of White British ancestry with no prior diagnosis of T2D and normal HbA levels. Using self-reported and hospital admission information, we deployed a machine learning procedure to select the most predictive and robust factors out of 111 nongenetically ascertained exposure and lifestyle variables for the PXS in prospective T2D. We computed the clinical risk score (CRS) and PGS by taking a weighted sum of eight established clinical risk factors and >6 million single nucleotide polymorphisms, respectively.

Results: In the study population, 7,513 had incident T2D. The C-statistics for the PGS, PXS, and CRS models were 0.709, 0.762, and 0.839, respectively. Individuals in the top 10% of PGS, PXS, and CRS had 2.00-, 5.90-, and 9.97-fold greater risk, respectively, compared to the remaining population. Addition of PGS and PXS to CRS improved T2D classification accuracy, with a continuous net reclassification index of 15.2% and 30.1% for cases, respectively, and 7.3% and 16.9% for controls, respectively.

Conclusions: For T2D, the PXS provides modest incremental predictive value over established clinical risk factors. However, the concept of PXS merits further consideration in T2D risk stratification and is likely to be useful in other chronic disease risk prediction models.
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http://dx.doi.org/10.2337/dc20-2049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985424PMC
April 2021

Education, biological ageing, all-cause and cause-specific mortality and morbidity: UK biobank cohort study.

EClinicalMedicine 2020 Dec 19;29-30:100658. Epub 2020 Nov 19.

Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, Netherlands.

Background: Socioeconomic position as measured by education may be embodied and affect the functioning of key physiological systems. Links between social disadvantage, its biological imprint, and cause-specific mortality and morbidity have not been investigated in large populations, and yet may point towards areas for public health interventions beyond targeting individual behaviours.

Methods: Using data from 366,748 UK Biobank participants with 13 biomarker measurements, we calculated a Biological Health Score (BHS, ranging from 0 to 1) capturing the level of functioning of five physiological systems. Associations between BHS and incidence of cardiovascular disease (CVD) and cancer, and mortality from all, CVD, cancer, and external causes were examined. We explored the role of education in these associations. Mendelian randomisation using genetic evidence was used to triangulate these findings.

Findings: An increase in BHS of 0.1 was associated with all-cause (HR = 1.14 [1.12-1.16] and 1.09 [1.07-1.12] in men and women respectively), cancer (HR = 1.11 [1.09-1.14] and 1.07 [1.04-1.10]) and CVD (HR = 1.25 [1.20-1.31] and 1.21 [1.11-1.31]) mortality, CVD incidence (HR = 1.15 [1.13-1.16] and 1.17 [1.15-1.19]). These associations survived adjustment for education, lifestyle-behaviours, body mass index (BMI), co-morbidities and medical treatments. Mendelian randomisation further supported the link between the BHS and CVD incidence (HR = 1.31 [1.21-1.42]). The BHS contributed to CVD incidence prediction (age-adjusted C-statistic = 0.58), other than through education and health behaviours.

Interpretation: The BHS captures features of the embodiment of education, health behaviours, and more proximal unknown factors which all complementarily contribute to all-cause, cancer and CVD morbidity and premature death.
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http://dx.doi.org/10.1016/j.eclinm.2020.100658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788440PMC
December 2020

Urate, Blood Pressure, and Cardiovascular Disease: Evidence From Mendelian Randomization and Meta-Analysis of Clinical Trials.

Hypertension 2021 02 28;77(2):383-392. Epub 2020 Dec 28.

Department of Epidemiology and Biostatistics, School of Public Health (D.G., V.K., V.Z., E.E., P.E., A.D., I.T.), Imperial College London, United Kingdom.

Serum urate has been implicated in hypertension and cardiovascular disease, but it is not known whether it is exerting a causal effect. To investigate this, we performed Mendelian randomization analysis using data from UK Biobank, Million Veterans Program and genome-wide association study consortia, and meta-analysis of randomized controlled trials. The main Mendelian randomization analyses showed that every 1-SD increase in genetically predicted serum urate was associated with an increased risk of coronary heart disease (odds ratio, 1.19 [95% CI, 1.10-1.30]; =4×10), peripheral artery disease (1.12 [95% CI, 1.03-1.21]; =9×10), and stroke (1.11 [95% CI, 1.05-1.18]; =2×10). In Mendelian randomization mediation analyses, elevated blood pressure was estimated to mediate approximately one-third of the effect of urate on cardiovascular disease risk. Systematic review and meta-analysis of randomized controlled trials showed a favorable effect of urate-lowering treatment on systolic blood pressure (mean difference, -2.55 mm Hg [95% CI, -4.06 to -1.05]; =1×10) and major adverse cardiovascular events in those with previous cardiovascular disease (odds ratio, 0.40 [95% CI, 0.22-0.73]; =3×10) but no significant effect on major adverse cardiovascular events in all individuals (odds ratio, 0.67 [95% CI, 0.44-1.03]; =0.07). In summary, these Mendelian randomization and clinical trial data support an effect of higher serum urate on increasing blood pressure, which may mediate a consequent effect on cardiovascular disease risk. High-quality trials are necessary to provide definitive evidence on the specific clinical contexts where urate lowering may be of cardiovascular benefit.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803439PMC
February 2021

Risk Prediction for Renal Cell Carcinoma: Results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 03 17;30(3):507-512. Epub 2020 Dec 17.

School of Public Health, Imperial College London, London, United Kingdom.

Background: Early detection of renal cell carcinoma (RCC) has the potential to improve disease outcomes. No screening program for sporadic RCC is in place. Given relatively low incidence, screening would need to focus on people at high risk of clinically meaningful disease so as to limit overdiagnosis and screen-detected false positives.

Methods: Among 192,172 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (including 588 incident RCC cases), we evaluated a published RCC risk prediction model (including age, sex, BMI, and smoking status) in terms of discrimination (C-statistic) and calibration (observed probability as a function of predicted probability). We used a flexible parametric survival model to develop an expanded model including age, sex, BMI, and smoking status, with the addition of self-reported history of hypertension and measured blood pressure.

Results: The previously published model yielded well-calibrated probabilities and good discrimination (C-statistic [95% CI]: 0.699 [0.679-0.721]). Our model had slightly improved discrimination (0.714 [0.694-0.735], bootstrap optimism-corrected C-statistic: 0.709). Despite this good performance, predicted risk was low for the vast majority of participants, with 70% of participants having 10-year risk less than 0.0025.

Conclusions: Although the models performed well for the prediction of incident RCC, they are currently insufficiently powerful to identify individuals at substantial risk of RCC in a general population.

Impact: Despite the promising performance of the EPIC RCC risk prediction model, further development of the model, possibly including biomarkers of risk, is required to enable risk stratification of RCC.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1438DOI Listing
March 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Neutrophil to lymphocyte ratio and cancer prognosis: an umbrella review of systematic reviews and meta-analyses of observational studies.

BMC Med 2020 11 20;18(1):360. Epub 2020 Nov 20.

Department of Epidemiology & Biostatistics, MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, W21PG, UK.

Background: Although neutrophils have been linked to the progression of cancer, uncertainty exists around their association with cancer outcomes, depending on the site, outcome and treatments considered. We aimed to evaluate the strength and validity of evidence on the association between either the neutrophil to lymphocyte ratio (NLR) or tumour-associated neutrophils (TAN) and cancer prognosis.

Methods: We searched MEDLINE, Embase and Cochrane Database of Systematic Reviews from inception to 29 May 2020 for systematic reviews and meta-analyses of observational studies on neutrophil counts (here NLR or TAN) and specific cancer outcomes related to disease progression or survival. The available evidence was graded as strong, highly suggestive, suggestive, weak or uncertain through the application of pre-set GRADE criteria.

Results: A total of 204 meta-analyses from 86 studies investigating the association between either NLR or TAN and cancer outcomes met the criteria for inclusion. All but one meta-analyses found a hazard ratio (HR) which increased risk (HR > 1). We did not find sufficient meta-analyses to evaluate TAN and cancer outcomes (N = 9). When assessed for magnitude of effect, significance and bias related to heterogeneity and small study effects, 18 (9%) associations between NLR and outcomes in composite cancer endpoints (combined analysis), cancers treated with immunotherapy and some site specific cancers (urinary, nasopharyngeal, gastric, breast, endometrial, soft tissue sarcoma and hepatocellular cancers) were supported by strong evidence.

Conclusion: In total, 60 (29%) meta-analyses presented strong or highly suggestive evidence. Although the NLR and TAN hold clinical promise in their association with poor cancer prognosis, further research is required to provide robust evidence, assess causality and test clinical utility.

Trial Registration: PROSPERO CRD42017069131 .
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http://dx.doi.org/10.1186/s12916-020-01817-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678319PMC
November 2020

Accelerated MRI-predicted brain ageing and its associations with cardiometabolic and brain disorders.

Sci Rep 2020 11 17;10(1):19940. Epub 2020 Nov 17.

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK.

Brain structure in later life reflects both influences of intrinsic aging and those of lifestyle, environment and disease. We developed a deep neural network model trained on brain MRI scans of healthy people to predict "healthy" brain age. Brain regions most informative for the prediction included the cerebellum, hippocampus, amygdala and insular cortex. We then applied this model to data from an independent group of people not stratified for health. A phenome-wide association analysis of over 1,410 traits in the UK Biobank with differences between the predicted and chronological ages for the second group identified significant associations with over 40 traits including diseases (e.g., type I and type II diabetes), disease risk factors (e.g., increased diastolic blood pressure and body mass index), and poorer cognitive function. These observations highlight relationships between brain and systemic health and have implications for understanding contributions of the latter to late life dementia risk.
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http://dx.doi.org/10.1038/s41598-020-76518-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672070PMC
November 2020

Early-Life Factors and Risk of Multiple Sclerosis: An MR-EWAS.

Neuroepidemiology 2020 23;54(6):433-445. Epub 2020 Oct 23.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece,

Background: Although several risk factors are associated with multiple sclerosis (MS) in adulthood, evidence for risk factors acting from birth to adolescence is scarce.

Methods: We conceived a 2-step study design, where signals from an Environment-Wide Association Study are prioritized for follow-up in a Mendelian Randomization study (MR-EWAS), to examine the association of early-life factors with risk of MS. The EWAS was conducted in UK Biobank, where we agnostically selected all the available risk factors acting from the perinatal period until the adolescence, including perinatal factors, anthropometric characteristics during childhood, male and female sexual factors, and skin phenotypic characteristics. We prioritized statistically significant risk factors to perform a 2-sample MR study using publicly available summary-level genetic data. We also calculated the power of the 2-step MR-EWAS approach under several scenarios and compared it against a 1-step hypothesis-free MR approach to detect risk factors of MS.

Results: In the EWAS, an increase per 1 year in age at menarche was associated with a lower risk of MS (OR = 0.93; 95% CI: 0.90-0.96) and a plumper than average body size at the age of 10 was associated with a higher risk of MS (OR = 1.42; 95% CI: 1.24-1.61). Individuals getting very tanned or moderately tanned were at higher risk of MS compared with individuals that never tan or get mildly to occasionally tanned (OR = 0.86; 95% CI: 0.79-0.94). The MR analysis supported the association of age at menarche and childhood body mass index (BMI) without presence of pleiotropic effects. In the multivariable MR analysis, the association of age at menarche was not statistically significant after adjusting for childhood BMI. The MR analysis for ease of tanning did not reveal a statistically significant association. In multiple scenarios, the power of MR-EWAS approach was larger than the power of a hypothesis-free MR approach.

Conclusions: We introduced the MR-EWAS, a 2-step approach that is more powerful compared with the hypothesis-free MR approach under certain scenarios, to test potential causal signals. Our comprehensive assessment of early-life risk factors of MS highlighted a potential causal role of early menarche and elevated childhood BMI for risk of MS.
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http://dx.doi.org/10.1159/000508229DOI Listing
September 2021

Weight change in middle adulthood and risk of cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Int J Cancer 2021 04 9;148(7):1637-1651. Epub 2020 Nov 9.

Unit of Cancer Epidemiology, Città della Salute e della Scienza University-Hospital and Center for Cancer Prevention (CPO), Turin, Italy.

Obesity is a risk factor for several major cancers. Associations of weight change in middle adulthood with cancer risk, however, are less clear. We examined the association of change in weight and body mass index (BMI) category during middle adulthood with 42 cancers, using multivariable Cox proportional hazards models in the European Prospective Investigation into Cancer and Nutrition cohort. Of 241 323 participants (31% men), 20% lost and 32% gained weight (>0.4 to 5.0 kg/year) during 6.9 years (average). During 8.0 years of follow-up after the second weight assessment, 20 960 incident cancers were ascertained. Independent of baseline BMI, weight gain (per one kg/year increment) was positively associated with cancer of the corpus uteri (hazard ratio [HR] = 1.14; 95% confidence interval: 1.05-1.23). Compared to stable weight (±0.4 kg/year), weight gain (>0.4 to 5.0 kg/year) was positively associated with cancers of the gallbladder and bile ducts (HR = 1.41; 1.01-1.96), postmenopausal breast (HR = 1.08; 1.00-1.16) and thyroid (HR = 1.40; 1.04-1.90). Compared to maintaining normal weight, maintaining overweight or obese BMI (World Health Organisation categories) was positively associated with most obesity-related cancers. Compared to maintaining the baseline BMI category, weight gain to a higher BMI category was positively associated with cancers of the postmenopausal breast (HR = 1.19; 1.06-1.33), ovary (HR = 1.40; 1.04-1.91), corpus uteri (HR = 1.42; 1.06-1.91), kidney (HR = 1.80; 1.20-2.68) and pancreas in men (HR = 1.81; 1.11-2.95). Losing weight to a lower BMI category, however, was inversely associated with cancers of the corpus uteri (HR = 0.40; 0.23-0.69) and colon (HR = 0.69; 0.52-0.92). Our findings support avoiding weight gain and encouraging weight loss in middle adulthood.
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http://dx.doi.org/10.1002/ijc.33339DOI Listing
April 2021

Dementia Incidence in the Elderly Population of Greece: Results From the HELIAD Study.

Alzheimer Dis Assoc Disord 2021 Jan-Mar 01;35(1):48-54

1st Department of Neurology, Aiginition Hospital, National and Kapodistrian University of Athens Medical School.

Objectives: Recently a declining trend in dementia incidence rates has been reported in high-income countries. We investigated dementia incidence in a representative sample of the Greek population in the age group of 65 years and above.

Methods: This research is part of the Hellenic Epidemiological Longitudinal Investigation of Aging and Diet (HELIAD). The incidence cohort consisted of 1072 participants who were reevaluated after a mean period of 3.09 years.

Results: The incidence rate of dementia was 19.0 cases per 1000 person-years (age-standardized and sex-standardized incidence: 25.4/1000 person-years), of which 16.3 per 1000 person-years were attributable to Alzheimer disease. Each additional year of age increased dementia risk by 19.3% and each additional year of education decreased dementia risk by 12.1%. Apolipoprotein E (APOE)-ε4 homozygous participants were 18 times more likely to be diagnosed with dementia. A baseline diagnosis of mild cognitive decline (MCI) resulted in a risk for dementia increased by 3.7 times compared with the cognitively normal; in participants with MCI at baseline, APOE-ε4 carriage increased dementia risk by 4.5 times.

Conclusions: The incidence rate of dementia in people 65 years and above in Greece is generally consistent with recently published rates in Europe and North America. Advancing age, baseline MCI, and APOE-ε4 homozygosity are risk factors, while higher educational attainment seems protective.
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http://dx.doi.org/10.1097/WAD.0000000000000407DOI Listing
October 2021

Global assessment of C-reactive protein and health-related outcomes: an umbrella review of evidence from observational studies and Mendelian randomization studies.

Eur J Epidemiol 2021 Jan 25;36(1):11-36. Epub 2020 Sep 25.

Department of Hygiene and Epidemiology, University of Ioannina Medical School, 45110, Ioannina, Greece.

C-reactive protein (CRP) has been studied extensively for association with a large number of non-infectious diseases and outcomes. We aimed to evaluate the breadth and validity of associations between CRP and non-infectious, chronic health outcomes and biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses and a systematic review of Mendelian randomization (MR) studies. PubMed, Scopus, and Cochrane Database of Systematic Reviews were systematically searched from inception up to March 2019. Meta-analyses of observational studies and MR studies examining associations between CRP and health outcomes were identified, excluding studies on the diagnostic value of CRP for infections. We found 113 meta-analytic comparisons of observational studies and 196 MR analyses, covering a wide range of outcomes. The overwhelming majority of the meta-analyses of observational studies reported a nominally statistically significant result (95/113, 84.1%); however, the majority of the meta-analyses displayed substantial heterogeneity (47.8%), small study effects (39.8%) or excess significance (41.6%). Only two outcomes, cardiovascular mortality and venous thromboembolism, showed convincing evidence of association with CRP levels. When examining the MR literature, we found MR studies for 53/113 outcomes examined in the observational study meta-analyses but substantial support for a causal association with CRP was not observed for any phenotype. Despite the striking amount of research on CRP, convincing evidence for associations and causal effects is remarkably limited.
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http://dx.doi.org/10.1007/s10654-020-00681-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847446PMC
January 2021

Scientific Opinion of the Scientific Panel on Plant Protection Products and their Residues (PPR Panel) on the genotoxic potential of triazine amine (metabolite common to several sulfonylurea active substances).

EFSA J 2020 Mar 9;18(3):e06053. Epub 2020 Mar 9.

The Panel received a mandate from the European Commission to assess the genotoxic potential of triazine amine based on available information submitted by the applicants. Available information includes experimental genotoxicity data on triazine amine, Quantitative Structure-Activity Relationship (QSAR) analysis and read across with structurally similar compounds. Based on the overall weight of evidence, the Panel, in agreement with the cross-cutting Working Group Genotoxicity, concluded that there is no concern for the potential of triazine amine to induce gene mutations and clastogenicity; however, the potential to induce aneugenicity was not adequately investigated. For a conclusion, an micronucleus assay performed with triazine amine would be needed.
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http://dx.doi.org/10.2903/j.efsa.2020.6053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447991PMC
March 2020

Risk factors for positive and negative COVID-19 tests: a cautious and in-depth analysis of UK biobank data.

Int J Epidemiol 2020 10;49(5):1454-1467

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

Background: The recent COVID-19 outbreak has generated an unprecedented public health crisis, with millions of infections and hundreds of thousands of deaths worldwide. Using hospital-based or mortality data, several COVID-19 risk factors have been identified, but these may be confounded or biased.

Methods: Using SARS-CoV-2 infection test data (n = 4509 tests; 1325 positive) from Public Health England, linked to the UK Biobank study, we explored the contribution of demographic, social, health risk, medical and environmental factors to COVID-19 risk. We used multivariable and penalized logistic regression models for the risk of (i) being tested, (ii) testing positive/negative in the study population and, adopting a test negative design, (iii) the risk of testing positive within the tested population.

Results: In the fully adjusted model, variables independently associated with the risk of being tested for COVID-19 with odds ratio >1.05 were: male sex; Black ethnicity; social disadvantage (as measured by education, housing and income); occupation (healthcare worker, retired, unemployed); ever smoker; severely obese; comorbidities; and greater exposure to particulate matter (PM) 2.5 absorbance. Of these, only male sex, non-White ethnicity and lower educational attainment, and none of the comorbidities or health risk factors, were associated with testing positive among tested individuals.

Conclusions: We adopted a careful and exhaustive approach within a large population-based cohort, which enabled us to triangulate evidence linking male sex, lower educational attainment and non-White ethnicity with the risk of COVID-19. The elucidation of the joint and independent effects of these factors is a high-priority area for further research to inform on the natural history of COVID-19.
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http://dx.doi.org/10.1093/ije/dyaa134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454561PMC
October 2020

Genetically predicted circulating concentrations of micronutrients and risk of breast cancer: A Mendelian randomization study.

Int J Cancer 2021 02 25;148(3):646-653. Epub 2020 Aug 25.

Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B , vitamin B and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10 ) higher risk of overall and ER breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.
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http://dx.doi.org/10.1002/ijc.33246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268064PMC
February 2021
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