Usefulness of Mendelian randomization in observational epidemiology.

Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. In this review, we recall the principles of a "Mendelian randomization" approach in observational epidemiology, which is based on the technique of instrumental variables; we provide simulations and an example based on real data to demonstrate its implications; we present the results of a systematic search on original articles having used this approach; and we discuss some limitations of this approach in view of what has been found so far.

Acute schistosomiasis outbreak in the metropolitan area of Belo Horizonte, Minas Gerais: alert about the risk of unnoticed transmission increased by growing rural tourism

The present article describes the occurrence of 17 cases of acute schistosomiasis in the metropolitan area of Belo Horizonte, state of Minas Gerais, Brazil. All individuals affected took a bath in a swimming pool of a holiday resort that was provided with water from a nearby brook. The apparently clean water and the absence of snails in the pool gave the wrong impression that there was no risk for infection. During a malacological survey at the site snails of the species Biomphalaria glabrata were found and tested positive for Schistosoma mansoni. All the patients live in the middle-class area of Barreiro, metropolitan area of Belo Horizonte and have medium grade school education. The difficulties in establishing the right diagnosis is expressed by the search for medical attention in 17 different medical facilities, the wide range of laboratory test and the inadequate treatment administration. A lack of knowledge about the disease was found in all groups studied. The booming rural tourism in endemic areas is identified as a probable risk factor for infection, especially for individuals of the non-immune middle and upper class parts of the society in urban centers. Special attention is given to a multidisciplinary approach to the complex issue of disease control and prevention.

Risk of hepatitis C among brazilian ex-soccer players

In order to evaluate the significance of injecting vitamins complexes and stimulants minutes before soccer games and its role in spread of hepatitis C virus (HCV) we interviewed and tested 40 ex-soccer players, who played professionally in Mato Grosso, Brazil, between 1970 and 1989. Five players were found anti-HCV positive with enzyme-immunoassay. When re-tested by imunoblot (RIBA), three of these five were confirmed to be positive reacting. The anti-HCV positivity (7.5%) was higher than usually found among blood donors (0.9%) in this region (p < 0.01). None of the players had had prior history of any risk factor that might indicate HCV exposure. We suggest that the common practice of soccer players in the inner part of Brazil in the 70's and 80's, to receive fortifying injections, often with shared syringes, may place ex-soccer players in a potencial risk group for HCV infection and warrants further investigation and attention by public health workers.

Current genetic data do not improve the prediction of type 2 diabetes mellitus: the CoLaus study.

CONTEXT: Several genetic risk scores to identify asymptomatic subjects at high risk of developing type 2 diabetes mellitus (T2DM) have been proposed, but it is unclear whether they add extra information to risk scores based on clinical and biological data. OBJECTIVE: The objective of the study was to assess the extra clinical value of genetic risk scores in predicting the occurrence of T2DM. DESIGN: This was a prospective study, with a mean follow-up time of 5 yr. SETTING AND SUBJECTS: The study included 2824 nondiabetic participants (1548 women, 52 ± 10 yr). MAIN OUTCOME MEASURE: Six genetic risk scores for T2DM were tested. Four were derived from the literature and two were created combining all (n = 24) or shared (n = 9) single-nucleotide polymorphisms of the previous scores. A previously validated clinic + biological risk score for T2DM was used as reference. RESULTS: Two hundred seven participants (7.3%) developed T2DM during follow-up. On bivariate analysis, no differences were found for all but one genetic score between nondiabetic and diabetic participants. After adjusting for the validated clinic + biological risk score, none of the genetic scores improved discrimination, as assessed by changes in the area under the receiver-operating characteristic curve (range -0.4 to -0.1%), sensitivity (-2.9 to -1.0%), specificity (0.0-0.1%), and positive (-6.6 to +0.7%) and negative (-0.2 to 0.0%) predictive values. Similarly, no improvement in T2DM risk prediction was found: net reclassification index ranging from -5.3 to -1.6% and nonsignificant (P ≥ 0.49) integrated discrimination improvement. CONCLUSIONS: In this study, adding genetic information to a previously validated clinic + biological score does not seem to improve the prediction of T2DM.

The prevalence of human immunodeficiency virus type 1 and hepatitis C virus among injection drug users who use high risk inner-city locales in Miami, Florida

In order to estimate the prevalence of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) co-infection in hard-to-reach intravenous drug users, 199 subjects from high-risk inner-city locales, the so called "shooting galleries", were consented, interviewed, and tested in Miami, FL, US. Positive HIV-1 status was based on repeatedly reactive ELISA and confirmatory Western Blot. Positive HCV status was based on reactive ELISA and confirmatory polymerase chain reaction techniques. Overall, 50 (25%) were not infected with either virus, 61 (31%) were HIV-1/HCV co-infected, 17 (8%) infected by HIV-1 only, and 71 (36%) infected by HCV only. The results of the multivariable analyses showed that more years using heroin was the only significant risk factor for HCV only infection (odds ratio = 1.15; 95% confidence interval = 1.07, 1.24) and for HIV-1/HCV co-infection (odds ratio = 1.17; 95% confidence interval = 1.09, 1.26). This paper demonstrates that HIV-1/HCV co-infection is highly prevalent among so called "shooting galleries".

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

BACKGROUND: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated. METHODS AND RESULTS: We exploited information made available by advanced new methods and resources in complex disease genetics to revisit the question of ESR1's role in risk of CAD. We performed a meta-analysis of 14 genome-wide association studies (CARDIoGRAM discovery analysis, N=≈87,000) to search for population-wide and sex-specific associations between CAD risk and common genetic variants throughout the coding, noncoding, and flanking regions of ESR1. In addition to samples from the MIGen (N=≈6000), WTCCC (N=≈7400), and Framingham (N=≈3700) studies, we extended this search to a larger number of common and uncommon variants by imputation into a panel of haplotypes constructed using data from the 1000 Genomes Project. Despite the widespread expression of ERα in vascular tissues, we found no evidence for involvement of common or low-frequency genetic variation throughout the ESR1 gene in modifying risk of CAD, either in the general population or as a function of sex. CONCLUSIONS: We suggest that future research on the genetic basis of sex-related differences in CAD risk should initially prioritize other genes in the reproductive steroid hormone biosynthesis system.

Alcohol and nonlethal injuries: a Swiss emergency department study on the risk relationship between acute alcohol consumption and type of injury.

BACKGROUND: Acute alcohol consumption has been reported to be an important risk factor for injury, but clear scientific evidence on issues such as injury type is not available. The present study aims to improve the knowledge of the importance of alcohol consumption as an injury determinant with regards to two dimensions of the type of injury, namely the nature and the body region involved. METHODS: Risk relationships between two injury type components and acute alcohol use were estimated through multinomial and logistic regression models based on data from 7,529 patients-among whom 3,682 had injury diagnoses-gathered in a Swiss emergency department. RESULTS: Depending on the type of injury, between 31.1% and 48.7% of casualties report alcohol use before emergency department attendance. The multinomial regression models show that even low alcohol levels are consistently associated with nearly all natures of injury and body regions. A persistent dose-response effect between alcohol levels and risk associations was observed for almost all injury types. CONCLUSIONS: The results highlight the importance and consistency of the risk association between low and moderate levels of acute alcohol consumption and all types of injury. None of the body regions and natures of injury could pride on absence of association between alcohol and injury. Public health, prevention, and care implications are considered.

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.

BACKGROUND: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. METHODS: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. FINDINGS: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. INTERPRETATION: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. FUNDING: UK Medical Research Council, US National Institutes of Health.

The prediction of cardiovascular events is improved by combination of Framingham risk score and subclinical atherosclerosis imaging

Purpose: In primary prevention of cardiovascular disease (CVD), it is accepted that the intensity of risk factor treatment should be guided by the magnitude of absolute risk. Risk factors tools like Framingham risk score (FHS) or noninvasive atherosclerosis imaging tests are available to detect high risk subjects. However, these methods are imperfect and may misclassify a large number of individuals. The purpose of this prospective study was to evaluate whether the prediction of future cardiovascular events (CVE) can be improved when subclinical imaging atherosclerosis (SCATS) is combined with the FRS in asymptomatic subjects. Methods: Overall, 1038 asymptomatic subjects (413 women, 625 men, mean age 49.1±12.8 years) were assessed for their cardiovascular risk using the FRS. B-mode ultrasonography on carotid and femoral arteries was performed by two investigators to detect atherosclerotic plaques (focal thickening of intima-media > 1.2 mm) and to measure carotid intima-media thickness (C-IMT). The severity of SCATS was expressed by an ATS-burden Score (ABS) reflecting the number of the arterial sites with >1 plaques (range 0-4). CVE were defined as fatal or non fatal acute coronary syndrome, stroke, or angioplasty for peripheral artery disease. Results: during a mean follow-up of 4.9±3.1 years, 61 CVE were recorded. Event rates the rate of CVE increased significantly from 2.7% to 39.1% according to the ABS (p<0.001) and from 4% to 24.6% according to the quartiles of C-IMT. Similarly, FRS predicted CVE (p<0.001). When computing the angiographic markers of SCATS in addition of FRS, we observed an improvement of net reclassification rate of 16.6% (p< 0.04) for ABS as compared to 5.5% (p = 0.26) for C-IMT. Conclusion: these results indicate that the detection of subjects requiring more attention to prevent CVE can be significantly improved when using both FRS and SCATS imaging.

Physicians' estimates of the 10 year cardiovascular risk in hypertensive patients: an evaluation in primary care physicians in training.

To evaluate how young physicians in training perceive their patients' cardiovascular risk based on the medical charts and their clinical judgment. Cross sectional observational study. University outpatient clinic, Lausanne, Switzerland. Two hundred hypertensive patients and 50 non-hypertensive patients with at least one cardiovascular risk factor. Comparison of the absolute 10-year cardiovascular risk calculated by a computer program based on the Framingham score and adapted for physicians by the WHO/ISH with the perceived risk as assessed clinically by the physicians. Physicians underestimated the 10-year cardiovascular risk of their patients compared to that calculated with the Framingham score. Concordance between methods was 39% for hypertensive patients and 30% for non-hypertensive patients. Underestimation of cardiovascular risks for hypertensive patients was related to the fact they had a stabilized systolic blood pressure under 140 mm Hg (OR = 2.1 [1.1; 4.1]). These data show that young physicians in training often have an incorrect perception of the cardiovascular risk of their patients with a tendency to underestimate the risk. However, the calculated risk could also be slightly overestimated when applying the Framingham Heart Study model to a Swiss population. To implement a systematic evaluation of risk factors in primary care a greater emphasis should be placed on the teaching of cardiovascular risk evaluation and on the implementation of quality improvement programs.

A preliminary evaluation of the validity of at-risk criteria for bipolar disorders in help-seeking adolescents and young adults.

INTRODUCTION: We have developed ultra-high risk criteria for bipolar affective disorder (bipolar at-risk - BAR) which include general criteria such as being in the peak age range of the onset of the disorder and a combination of specific criteria including sub-threshold mania, depressive symptoms, cyclothymic features and genetic risk. In the current study, the predictive validity of these criteria were tested in help-seeking adolescents and young adults. METHOD: This medical file-audit study was conducted at ORYGEN Youth Health (OYH), a public mental health program for young people aged between 15 and 24years and living in metropolitan Melbourne, Australia. BAR criteria were applied to the intake assessments of all non-psychotic patients who were being treated in OYH on 31 January, 2008. All entries were then checked for conversion criteria. Hypomania/mania related additions or alterations to existing treatments or initiation of new treatment by the treating psychiatrist served as conversion criteria to mania. RESULTS: The BAR criteria were applied to 173 intake assessments. Of these, 22 patients (12.7%) met BAR criteria. The follow-up period of the sample was 265.5days on average (SD 214.7). There were significantly more cases in the BAR group (22.7%, n=5) than in the non-BAR group (0.7%, n=1) who met conversion criteria (p<.001). CONCLUSIONS: These findings support the notion that people who develop a first episode of mania can be identified during the prodromal phase. The proposed criteria need further evaluation in prospective clinical trials.

Mandibular osteoradionecrosis in squamous cell carcinoma of the oral cavity and oropharynx: incidence and risk factors.

Objective. Mandibular osteoradionecrosis (ORN) is a serious complication of radiotherapy (RT) in head and neck cancer patients. The aim of this study was to analyze the incidence of and risk factors for mandibular ORN in squamous cell carcinoma (SCC) of the oral cavity and oropharynx.Study Design. Case series with chart review.Setting. University tertiary care center for head and neck oncology.Subjects and Methods. Seventy-three patients treated for stage I to IV SCC of the oral cavity and oropharynx between 2000 and 2007, with a minimum follow-up of 2 years, were included in the study. Treatment modalities included both RT with curative intent and adjuvant RT following tumor surgery. The log-rank test and Cox model were used for univariate and multivariate analyses.Results. The incidence of mandibular ORN was 40% at 5 years. Using univariate analysis, the following risk factors were identified: oral cavity tumors (P < .01), bone invasion (P < .02), any surgery prior to RT (P < .04), and bone surgery (P < .0001). By multivariate analysis, mandibular surgery proved to be the most important risk factor and the only one reaching statistical significance (P < .0002).Conclusion. Mandibular ORN is a frequent long-term complication of RT for oral cavity and oropharynx cancers. Mandibular surgery before irradiation is the only independent risk factor. These aspects must be considered when planning treatment for these tumors.

A meta-analysis of the association of fracture risk and body mass index in women.

Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20-105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m(2) ) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m(2) , the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m(2) was 0.87 (95% confidence interval [CI], 0.85-0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09-1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.

Body mass index, abdominal adiposity and blood pressure: consistency of their association across developing and developed countries.

BACKGROUND: Obesity is increasing worldwide because developing countries are adopting Western high-fat foods and sedentary lifestyles. In parallel, in many of them, hypertension is rising more rapidly, particularly with age, than in Western countries. OBJECTIVE: To assess the relationship between adiposity and blood pressure (BP) in a developing country with high average BP (The Seychelles, Indian Ocean, population mainly of African origin) in comparison to a developed country with low average BP (Switzerland, population mainly of Caucasian origin). DESIGN: Cross-sectional health examination surveys based on population random samples. SETTING: The main Seychelles island (Mahé) and two Swiss regions (Vaud-Fribourg and Ticino). SUBJECTS: Three thousand one hundred and sixteen adults (age range 35-64) untreated for hypertension. MEASUREMENTS: Body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), systolic and diastolic blood pressure (SBP and DBP, mean of two measures). METHODS: Scatterplot smoothing techniques and gender-specific linear regression models. RESULTS: On average, SBP and DBP were found to increase linearly over the whole variation range of BMI, WHR and WC. A modest, but statistically significant linear association was found between each indicator of adiposity and BP levels in separate regression models controlling for age. The regression coefficients were not significantly different between the Seychelles and the two Swiss regions, but were generally higher in women than in men. For the latter, a gain of 1.7 kg/m(2) in BMI, of 4.5 cm in WC or of 3.4% in WHR corresponded to an elevation of 1 mmHg in SBP. For women, corresponding figures were 1.25 kg/m(2), 2.5 cm and 1.8% respectively. Regression coefficients for age reflected a higher effect of this variable on both SBP and DBP in the Seychelles than in Switzerland. CONCLUSION: These findings suggest a stable linear relation of adiposity with BP, independent of age and body fat distribution, across developed and developing countries. The more rapid increase of BP with age observed in the latter countries are likely to reflect higher genetic susceptibility and/or higher cumulative exposure to another risk factor than adiposity.

Human Exposure to Endocrine-Disrupting Chemicals and Prenatal Risk Factors for Cryptorchidism and Hypospadias: A Nested Case-Control Study

BACKGROUND. Exposure to xenoestrogens during pregnancy may disturb the development and function of male sexual organs. OBJECTIVE. In this study we aimed to determine whether the combined effect of environmental estrogens measured as total effective xenoestrogen burden (TEXB) is a risk factor for male urogenital malformations. METHODS. In a case-control study, nested in a mother-child cohort (n = 702) established at Granada University Hospital, we compared 50 newborns with diagnosis of cryptorchidism and/or hypospadias with 114 boys without malformations matched by gestational age, date of birth, and parity. Controls did not differ from the total cohort in confounding variables. TEXB and levels of 16 organochlorine pesticides were measured in placenta tissues. Characteristics of parents, pregnancy, and birth were gathered by questionnaire. We used conditional and unconditional regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS. TEXB from organohalogenated compounds was detectable in 72% and 54% of case and control placentas, respectively. Compared with controls, cases had an OR for detectable versus non-detectable TEXB of 2.82 (95% CI, 1.10-7.24). More pesticides were detected in cases than in controls (9.34 +/- 3.19 vs. 6.97 +/- 3.93). ORs for cases with detectable levels of pesticides, after adjusting for potential confounders in the conditional regression analysis, were o,p'-DDT (OR = 2.25; 95% CI, 1.03-4.89), p,p'-DDT (OR = 2.63; 95% CI, 1.21-5.72), lindane (OR = 3.38; 95% CI, 1.36-8.38), mirex (OR = 2.85; 95% CI, 1.22-6.66), and endosulfan alpha (OR = 2.19; 95% CI, 0.99-4.82). Engagement of mothers in agriculture (OR = 3.47; 95% CI, 1.33-9.03), fathers' occupational exposure to xenoestrogens (OR = 2.98; 95% CI, 1.11-8.01), and history of previous stillbirths (OR = 4.20; 95% CI, 1.11-16.66) were also associated with risk of malformations. CONCLUSIONS We found an increased risk for male urogenital malformations related to the combined effect of environmental estrogens in placenta.