Primary prevention from the epidemiology perspective: three examples from the practice

Background: Primary prevention programmes are of increasing importance to reduce the impact of chronic diseases on the individual, institutional and societal level. However, most initiatives that develop and implement primary prevention programmes are not evaluated with scientific rigor. On the basis of three different projects we discuss necessary steps on the road to evidence-based primary prevention. Discussion: We first discuss how to identify suitable target groups exploiting sophisticated statistical methods. This is illustrated using data from a health survey conducted in a federal state of Germany. A literature review is the more typical approach to identify target groups that is demonstrated using a European project on the prevention of childhood obesity. In the next step, modifiable risk factors and realistic targets of the intervention have to be specified. These determine the outcome measures that in turn are used for effect evaluation. Both, the target groups and the outcome measures, lay the ground for the study design and the definition of comparison groups as can be seen in our European project. This project also illustrates the development and implementation of a prevention programme. These may require active involvement of participants which can be achieved by participatory approaches taking into account the socio-cultural and living environment. Evaluation is of utmost importance for any intervention to assess structure, process and outcome according to rigid scientific criteria. Different approaches used for this are discussed and illustrated by a methodological project developed within a health promotion programme in a deprived area. Eventually the challenge of transferring an evidence-based intervention into practice and to achieve its sustainability is addressed. Summary: This article describes a general roadmap to primary prevention comprising (1) the identification of target groups and settings, (2) the identification of modifiable risk factors and endpoints, (3) the development and implementation of an intervention programme, (4) the evaluation of structure, process and outcome and (5) the transfer of an evidence-based intervention into practice

Socioeconomic inequalities in cancer incidence and mortality - a spatial analysis in Bremen, Germany

Aim: Several international studies have already investigated the influence of socioeconomic factors on the risk of cancer. For Germany, however, the data are still insufficient. We examined the effects of social differences on cancer incidence and mortality on the population of Bremen, a town in northwest Germany. Subjects and methods: Data were obtained from the Bremen Cancer Registry, a population-based registry. The database comprised 27,430 incident cases, newly diagnosed between 2000 and 2006. The allocation of social class for each patient was based on the home address at the time of diagnosis, which led to the corresponding town district, which again could be linked to the “Bremen discrimination index.” Based on this index, cases were allocated to five categories, for which we compared standardized incidence ratios (SIR) and mortality ratios (SMR) for different cancers: prostate, breast, lung, colorectal, bladder, uterine, ovarian, cervical, malignant melanoma of the skin, non-melanoma skin cancer and all cancer sites summarized. Results: The influence of social status was observed for different cancer sites. An inverse association was ascertained for all cancer sites (only men) and for tumors of the oral cavity and pharynx, and for lung, cervical and bladder cancers. A positive correlation was observed for female breast cancer, malignant melanoma, non-melanoma skin tumors and prostate cancer. Conclusions: In spite of the methodical restrictions, our analyses suggest an association between social factors and cancer incidence and mortality. The results are in agreement with international studies. Many of the observed social class differences could probably be explained by known risk factors, such as smoking, alcohol consumption, diet and physical activity

The role of neuromedin U in adiposity regulation. Haplotype analysis in European children from the IDEFICS Cohort

Background and aims: Neuromedin U (NMU) is a hypothalamic neuropeptide with important roles in several metabolic processes, recently suggested as potential therapeutic target for obesity. We analysed the associations between NMU gene variants and haplotypes and body mass index (BMI) in a large sample of European children. Methods and results: From a large European multi-center study on childhood obesity, 4,528 children (2.0–9.9 years, mean age 6.0±1.8 SD; boys 52.2%) were randomly selected, stratifying by age, sex and country, and genotyped for tag single nucleotide polymorphisms (SNPs; rs6827359, T:C; rs12500837, T:C; rs9999653,C:T) of NMU gene, then haplotypes were inferred. Regression models were applied to estimate the associations between SNPs or haplotypes and BMI as well as other anthropometric measures. BMI was associated with all NMU SNPs (p<0.05). Among five haplotypes inferred, the haplotype carrying the minor alleles (CCT, frequency = 22.3%) was the only associated with lower BMI values (beta = -0.16, 95%CI:-0.28,-0.04, p = 0.006; z-score, beta = -0.08, 95%CI:-0.14,-0.01, p = 0.019) and decreased risk of overweight/obesity (OR = 0.81, 95%CI:0.68,0.97, p = 0.020) when compared to the most prevalent haplotype (codominant model). Similar significant associations were also observed using the same variables collected after two years’ time (BMI, beta = -0.25, 95%CI:-0.41,-0.08, p = 0.004; z-score, beta = -0.10, 95%CI:-0.18,-0.03, p = 0.009; overweight/obesity OR = 0.81, 95%CI:0.66,0.99, p = 0.036). The association was age-dependent in girls (interaction between CCT haplotypes and age, p = 0.008), more evident between 7 and 9 years of age. The CCT haplotype was consistently associated with lower levels of fat mass, skinfold thickness, hip and arm circumferences both at T0 and at T1, after adjustment for multiple testing (FDR-adjusted p<0.05). Conclusions: This study shows an association between a NMU haplotype and anthropometric indices, mainly linked to fat mass, which appears to be age- and sex-specific in children. Genetic variations within or in linkage with this haplotype should be investigated to identify functional variants responsible for the observed phenotypic variation

The temporal relationship between parental concern of overeating and childhood obesity considering genetic susceptibility : longitudinal results from the IDEFICS/I.Family study

Background: Many genes and molecular pathways are associated with obesity, but the mechanisms from genes to obesity are less well known. Eating behaviors represent a plausible pathway, but because the relationships of eating behaviors and obesity may be bi-directional, it remains challenging to resolve the underlying pathways. A longitudinal approach is needed to assess the contribution of genetic risk during the development of obesity in childhood. In this study we aim to examine the relationships between the polygenic risk score for body mass index (PRS-BMI), parental concern of overeating and obesity indices during childhood. Methods: The IDEFICS/I.Family study is a school-based multicenter pan-European cohort of children observed for 6 years (mean +/- SD follow-up 5.8 +/- 0.4). Children examined in 2007/2008 (wave 1) (mean +/- SD age: 4.4 +/- 1.1, range: 2-9 years), in 2009/2010 (wave 2) and in 2013/2014 (wave 3) were included. A total of 5112 children (49% girls) participated at waves 1, 2 and 3. For 2656 children with genome-wide data we constructed a PRS based on 2.1 million single nucleotide polymorphisms. Z-score BMI and z-score waist circumference (WC) were assessed and eating behaviors and relevant confounders were reported by parents via questionnaires. Parental concern of overeating was derived from principal component analyses from an eating behavior questionnaire. Results: In cross-lagged models, the prospective associations between z-score obesity indices and parental concern of overeating were bi-directional. In mediation models, the association between the PRS-BMI and parental concern of overeating at wave 3 was mediated by baseline z-BMI (beta = 0.16, 95% CI: 0.10, 0.21) and baseline z-WC (beta = 0.17, 95% CI: 0.11, 0.23). To a lesser extent, baseline parental concern of overeating also mediated the association between the PRS-BMI and z-BMI at wave 3 (beta = 0.10, 95% CI: 0.07, 0.13) and z-WC at wave 3 (beta = 0.09, 95% CI: 0.07, 0.12). Conclusions: The findings suggest that the prospective associations between obesity indices and parental concern of overeating are likely bi-directional, but obesity indices have a stronger association with future parental concern of overeating than vice versa. The findings suggest parental concern of overeating as a possible mediator in the genetic susceptibility to obesity and further highlight that other pathways are also involved. A better understanding of the genetic pathways that lead to childhood obesity can help to prevent weight gain.Peer reviewe

Transcriptome analysis in blood cells from children reveals potential early biomarkers of metabolic alterations

OBJECTIVES: The development of effective strategies to prevent childhood obesity and its comorbidities requires new, reliable early biomarkers. Here, we aimed to identify in peripheral blood cells potential transcript-based biomarkers of unhealthy metabolic profile associated to overweight/obesity in children. METHODS: We performed a whole-genome microarray analysis in blood cells to identify genes differentially expressed between overweight and normal weight children to obtain novel transcript-based biomarkers predictive of metabolic complications. RESULTS: The most significant enriched pathway of differentially expressed genes was related to oxidative phosphorylation, for which most of genes were downregulated in overweight versus normal weight children. Other genes were involved in carbohydrate metabolism/glucose homoeostasis or in lipid metabolism (for example, TCF7L2, ADRB3, LIPE, GIPR), revealing plausible mechanisms according to existing biological knowledge. A set of differentially expressed genes was identified to discriminate in overweight children those with high or low triglyceride levels. CONCLUSIONS: Functional microarray analysis has revealed a set of potential blood-cell transcript-based biomarkers that may be a useful approach for early identification of children with higher predisposition to obesity-related metabolic alterations

In atrial fibrillation epilepsy risk differs between oral anticoagulants: active comparator, nested case-control study

AIMS: Atrial fibrillation (AF) is a risk factor for brain infarction, which can lead to epilepsy. We aimed to investigate whether treatment of AF with direct oral anticoagulants (DOACs) affects the risk of epilepsy in comparison to treatment with the vitamin K antagonist phenprocoumon (PPC). METHODS AND RESULTS: We performed an active comparator, nested case-control study based on the German Pharmacoepidemiological Research Database that includes claims data from statutory health insurance providers of about 25 million persons since 2004. In 2011-17, 227 707 AF patients initiated treatment with a DOAC or PPC, of which 1828 cases developed epilepsy on current treatment with an oral anticoagulant. They were matched to 19 084 controls without epilepsy. Patients with DOAC treatment for AF had an overall higher risk of epilepsy with an odds ratio of 1.39, 95% CI (1.24; 1.55) compared to current PPC treatment. Cases had higher baseline CHA2DS2-VASc scores and more frequently a history of stroke than controls. After excluding patients with ischaemic stroke prior to the diagnosis of epilepsy, the risk of epilepsy was still higher on DOACs than on PPC. In contrast, within a cohort of patients with venous thromboembolism, the risk of epilepsy on treatment with DOACs was less elevated [adjusted odds ratio 1.15, 95% CI (0.98; 1.34)]. CONCLUSION: In patients with AF initiating oral anticoagulation, treatment with a DOAC was associated with an increased risk of epilepsy compared to the vitamin K antagonist PPC. Covert brain infarction may explain the observed elevated risk of epilepsy

Reference values for leptin and adiponectin in children below the age of 10 based on the IDEFICS cohort

OBJECTIVE: To establish age- and sex-specific reference values for serum leptin and adiponectin in normal-weight 3.0-8.9-year old European children. SUBJECTS AND METHODS: Blood samples for hormone analysis were taken from 1338 children of the IDEFICS (Identification and prevention of Dietary-and lifestyle-induced health Effects in Children and infantS) study cohort. Only normal-weight children aged 3.0-8.9 years were included (n = 539) in our analysis. Using the General Additive Model for Location Scale and Shape, age-and sex-specific percentiles were derived. The influence of under/overweight and obesity on the proposed reference curves based on normal-weight children was investigated in several sensitivity analyses using the sample without obese children (n = 1015) and the whole study sample (n = 1338). RESULTS: There was a negative age trend of adiponectin blood levels and a positive trend of leptin levels in boys and girls. Percentiles derived for girls were generally higher than those obtained for boys. The corresponding age-specific differences of the 97th percentile ranged from -2.2 to 4.6 mu g ml(-1) and from 2.2 to 4.8 ng ml(-1) for adiponectin and leptin, respectively. CONCLUSIONS: According to our knowledge, these are the first reference values of leptin and adiponectin in prepubertal, normal-weight children. The presented adiponectin and leptin reference curves may allow for a more differentiated interpretation of children's hormone levels in epidemiological and clinical studies

Longitudinal association of inflammatory markers with markers of glycaemia and insulin resistance in European children

Purpose: Subclinical systemic inflammation may lead to development of type 2 diabetes, but there has been no investigation into its relationship with early progression of glycaemic deterioration and insulin resistance, especially in younger population. In this study we assessed longitudinal associations of pro- and anti-inflammatory markers with markers that evaluate glycaemia and insulin resistance. Methods: This study includes 6537 initially nondiabetic children (mean age at baseline = 6.2 years) with repeated measurements from the IDEFICS/I.Family cohort study (mean follow-up = 5.3 years) from eight European countries. Markers of inflammation were used as independent variables and markers of glycaemia/insulin resistance as dependent variables. Associations were examined using two-level growth model. Models were adjusted for sex, age, major lifestyle, metabolic risk factors, early life markers, and other inflammatory markers in final model. Results: Children with 6 years of follow-up showed that a one-unit increase in z-score of leptin level was associated with 0.38 (95% CI = 0.32 to 0.44) unit increase in HOMA-IR z-scores. Leptin continued to be associated with HOMA-IR even when analysis was limited to children with no overall obesity, no abdominal obesity, and low to normal triglyceride levels. An inverse association was observed between IL-15 and HOMA-IR (ß = -0.11, 95% CI = -0.15 to -0.07). Conclusions: IL-15 should be evaluated further in the prevention or treatment of prediabetes whereas leptin may prove to be useful in early detection of prediabetes via their association with markers of insulin resistance in European children

Peer Effects on Weight Status, Dietary Behaviour and Physical Activity among Adolescents in Europe: Findings from the I.Family Study

This study uses survey data from the I.Family Study to investigate the association between adolescent and peer overweight in a sample of adolescents aged 12–16 from six European countries. We find clear evidence of peer effects on body mass index, waist circumference, and body fat, which are stronger among adolescents at the upper end of overweight distribution. We also provide evidence that both consumption of less healthy foods and time spent in leisure time physical activity and audio-visual media are positively associated with similar behaviours among friends. These observations may suggest that peer effects on adolescent overweight operate by influencing friends’ behaviour patterns, especially unhealthy food consumption and physical (in)activity

The role of a FADS1 polymorphism in the association of fatty acid blood levels, BMI and blood pressure in young children-Analyses based on path models

Background The recent obesity epidemic in children also showed an increase in the prevalence of hypertension. As blood pressure (BP) is associated with (long-chain) polyunsaturated fatty acids (LC PUFA), genetic variation in desaturase enzymes being involved in the synthesis of LC PUFA may be associated with BP. This study aimed to investigate the direct effects (independent of mediating variables) and indirect effects (mediated through intermediate variables) of a common variant in the FADS1 gene, rs174546, known to affect delta-5 desaturase (D5D) activity on PUFA level, body mass index (BMI) and BP. Methods A subsample of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) baseline survey including 520 children aged 2 to Results Minor allele carriers of the SNP rs174546 had significantly higher DGLA and lower ARA and EPA levels as well as a lower D5D index. Via ARA and BMI z-score, the polymorphism had an indirect lowering effect on systolic BP z-score for each additional T allele (standardized effect estimate -0.057, p = 0.007). For DGLA, EPA and D5D index, the indirect effects of rs174546 on systolic BP were also negative but did not reach significance. DGLA and EPA had an increasing indirect effect on systolic BP via BMI. Results for diastolic BP were in general similar but effect estimates were lower compared to systolic BP. Conclusion Genetic variation in FADS1 influences BP via ARA and BMI indicating a favorable effect of the minor allele in SNP rs174546. Thus, polymorphisms with an impact on the D5D activity may play a role for the BP level mediated through PUFA and BMI. Therefore, health effects of dietary n-6 and n-3 PUFA may vary depending on genetic FADS1 variants.Peer reviewe