Effect of metabolic genetic variants on long-term disease comorbidity in patients with type 2 diabetes.

Underlying genetic determinants contribute to developing type 2 diabetes (T2D) future diseases. The present study aimed to identify which genetic variants are associated with the incident of the major T2D co-morbid disease. First, we conducted a discovery study by investigating the genetic associations of comorbid diseases within the framework of the Utrecht Cardiovascular Pharmacogenetic studies by turning information of > 25 years follow-up data of 1237 subjects whom were genotyped and included in the discovery study. We performed Cox proportional-hazards regression to examine associations between genetic variants and comorbid diseases including cardiovascular diseases (CVD), chronic eye disease, cancer, neurologic diseases and chronic kidney disease. Secondly, we replicated our findings in two independent cohorts consisting of 1041 subjects. Finally, we performed a meta-analysis by combining the discovery and two replication cohorts. We ascertained 390 (39.7%) incident cases of CVD, 182 (16.2%) of chronic eye disease, 155 (13.8%) of cancer, 31 (2.7%) of neurologic disease and 13 (1.1%) of chronic kidney disease during a median follow-up of 10.2 years. In the discovery study, we identified a total of 39 Single Nucleotide Polymorphisms (SNPs) associated with comorbid diseases. The replication study, confirmed that rs1870849 and rs8051326 may play a role in the incidence of chronic eye disease in T2D patients. Half of patients developed at least one comorbid disease, with CVD occurring most often and earliest followed by chronic eye disease. Further research is needed to confirm the associations of two associated SNPs with chronic eye disease in T2D.

Factors of physical activity among Chinese children and adolescents: a systematic review.

BACKGROUND: Lack of physical activity is a growing problem in China, due to the fast economic development and changing living environment over the past two decades. The aim of this review is to summarize the factors related to physical activity in Chinese children and adolescents during this distinct period of development. METHODS: A systematic search was finished on Jan 10th, 2017, and identified 2200 hits through PubMed and Web of Science. English-language published studies were included if they reported statistical associations between factors and physical activity. Adapted criteria from the Strengthening The Reporting of OBservational studies in Epidemiology (STROBE) statement and evaluation of the quality of prognosis studies in systematic reviews (QUIPS) were used to assess the risk of bias of the included studies. Related factors that were reported in at least three studies were summarized separately for children and adolescents using a semi-quantitative method. RESULTS: Forty two papers (published 2002-2016) were included. Most designs were cross-sectional (79%), and most studies used questionnaires to assess physical activity. Sample size was above 1000 in 18 papers (43%). Thirty seven studies (88%) showed acceptable quality by methodological quality assessment. Most studies reported a low level of physical activity. Boys were consistently more active than girls, the parental physical activity was positively associated with children and adolescents' physical activity, children in suburban/rural regions showed less activity than in urban regions, and, specifically in adolescents, self-efficacy was positively associated with physical activity. Family socioeconomic status and parental education were not associated with physical activity in children and adolescents. CONCLUSIONS: The studies included in this review were large but mostly of low quality in terms of study design (cross-sectional) and methods (questionnaires). Parental physical activity and self-efficacy are promising targets for future physical activity promotion programmes. The low level of physical activity raises concern, especially in suburban/rural regions. Future research is required to enhance our understanding of other influences, such as the physical environment, especially in early childhood.

The LifeLines Cohort Study: Prevalence and treatment of cardiovascular disease and risk factors.

BACKGROUND: The LifeLines Cohort Study is a large three-generation prospective study and Biobank. Recruitment and data collection started in 2006 and follow-up is planned for 30years. The central aim of LifeLines is to understand healthy ageing in the 21st century. Here, the study design, methods, baseline and major cardiovascular phenotypes of the LifeLines Cohort Study are presented. METHODS AND RESULTS: Baseline cardiovascular phenotypes were defined in 9700 juvenile (8-18years) and 152,180 adult (≥18years) participants. Cardiovascular disease (CVD) was defined using ICD-10 criteria. At least one cardiovascular risk factor was present in 73% of the adult participants. The prevalence, adjusted for the Dutch population, was determined for risk factors (hypertension (33%), hypercholesterolemia (19%), diabetes (4%), overweight (56%), and current smoking (19%)) and CVD (myocardial infarction (1.8%), heart failure (1.0%), and atrial fibrillation (1.3%)). Overall CVD prevalence increased with age from 9% in participants<65years to 28% in participants≥65years. Of the participants with hypertension, hypercholesterolemia and diabetes, respectively 75%, 96% and 41% did not receive preventive pharmacotherapy. CONCLUSIONS: The contemporary LifeLines Cohort Study provides researchers with unique and novel opportunities to study environmental, phenotypic, and genetic risk factors for CVD and is expected to improve our knowledge on healthy ageing. In this contemporary Western cohort we identified a remarkable high percentage of untreated CVD risk factors suggesting that not all opportunities to reduce the CVD burden are utilised.

The relationship between social functioning and subjective memory complaints in older persons: a population-based longitudinal cohort study.

OBJECTIVE: Poor social functioning is associated with cognitive decline in older adults. It is unclear whether social functioning is also associated with subjective memory complaints (SMC). We investigated the association between social functioning and incident SMC and SMC recovery. METHODS: A population-based sample of 8762 older adults (aged ≥65 years) with good objective cognitive functioning at baseline (MMSE ≥26) from the LifeLines Cohort Study were followed for 1.5 years. Self-reported SMC were measured at baseline and after 1.5 years follow-up. Aspects of social functioning included marital status, household composition, social network size, social activity, quality of social relationships, social support, affection, behavioral confirmation, and status. RESULTS: Thirteen percent (513/3963) developed SMC during follow-up (incident SMC). Multivariate logistic regression analyses (adjusted for age, gender, education level, physical activity, alcohol use, smoking status, depression, arrhythmia, myocardial infarction, heart failure, stroke) showed that participants with better feelings of affection, behavioral confirmation and stable good social support had a lower risk of incident SMC. Thirty-four percent (1632/4799) reported recovery. Participants with good social functioning at baseline on all determinants reported more SMC recovery. People who remained stable in a relationship, stable in good quality of social relationships or increased in quality of social relationships more often report SMC recovery. CONCLUSIONS: Good social functioning is associated with less incident SMC and more SMC recovery over a follow-up period of 1.5 years. Albeit future confirmative studies are needed, we argue for targeting also social functioning when designing multidomain interventions to prevent or slow down cognitive decline. Copyright © 2016 John Wiley & Sons, Ltd.

Eosinophil Count Is a Common Factor for Complex Metabolic and Pulmonary Traits and Diseases: The LifeLines Cohort Study.

There is ongoing debate on the association between eosinophil count and diseases, as previous studies were inconsistent. We studied the relationship of eosinophil count with 22 complex metabolic, cardiac, and pulmonary traits and diseases. From the population-based LifeLines Cohort Study (N = 167,729), 13,301 individuals were included. We focused on relationship of eosinophil count with three classes of metabolic (7 traits, 2 diseases), cardiac (6 traits, 2 diseases), and pulmonary (2 traits, 2 diseases) outcomes. Regression analyses were applied in overall, women and men, while adjusted for age, sex, BMI and smoking. A p-value of <0.00076 was considered statistically significant. 58.2% of population were women (mean±SD 51.3±11.1 years old). In overall, one-SD higher of ln-eosinophil count was associated with a 0.04 (±SE ±0.002;p = 6.0×10-6) SD higher levels in ln-BMI, 0.06 (±0.007;p = 3.1×10-12) SD in ln-TG, 0.04 (±0.003;p = 7.0×10-6) SD in TC, 0.04 (±0.004;p = 6.3×10-7) SD in LDL, 0.04 (±0.006;p = 6.0×10-6) SD in HbA1c; and with a 0.05 (±0.004;p = 1.7×10-8) SD lower levels in HDL, 0.05 (±0.007;p = 3.4×10-23) SD in FEV1, and 0.09 (±0.001;p = 6.6×10-28) SD in FEV1/FVC. A higher ln-eosinophil count was associated with 1.18 (95%CI 1.09-1.28;p = 2.0×10-5) odds ratio of obesity, 1.29 (1.19-1.39;p = 1.1×10-10) of metabolic syndrome, 1.40 (1.25-1.56;p = 2.7×10-9) of COPD and 1.81 (1.61-2.03;p = 1.0×10-23) of asthma. Similar results were found in women. We found no association between ln-eosinophil count either with blood pressure indices in overall, women and men; or with BMI, LDL, HbA1c and obesity in men. In a large population based cohort, we confirmed eosinophil count as a potential factor implicated in metabolic and pulmonary outcomes.

Effect of diagnosis with a chronic disease on physical activity behavior in middle-aged women.

OBJECTIVE: Although regular physical activity is an effective secondary prevention strategy for patients with a chronic disease, it is unclear whether patients change their daily physical activity after being diagnosed. Therefore, the aims of this study were to (1) describe changes in levels of physical activity in middle-aged women before and after diagnosis with a chronic disease (heart disease, diabetes, asthma, breast cancer, arthritis, depression); and to (2) examine whether diagnosis with a chronic disease affects levels of physical activity in these women. METHODS: Data from 5 surveys (1998-2010) of the Australian Longitudinal Study on Women's Health (ALSWH) were used. Participants (N=4840, born 1946-1951) completed surveys every three years, with questions about diseases and leisure time physical activity. The main outcome measure was physical activity, categorized as: nil/sedentary, low active, moderately active, highly active. RESULTS: At each survey approximately half the middle-aged women did not meet the recommended level of physical activity. Between consecutive surveys, 41%-46% of the women did not change, 24%-30% decreased, and 24%-31% increased their physical activity level. These proportions of change were similar directly after diagnosis with a chronic disease, and in the years before or after diagnosis. Generalized estimating equations showed that there was no statistically significant effect of diagnosis with a chronic disease on levels of physical activity in women. CONCLUSION: Despite the importance of physical activity for the management of chronic diseases, most women did not increase their physical activity after diagnosis. This illustrates a need for tailored interventions to enhance physical activity in newly diagnosed patients.

(Un)Healthy in the City: Respiratory, Cardiometabolic and Mental Health Associated with Urbanity.

BACKGROUND: Research has shown that health differences exist between urban and rural areas. Most studies conducted, however, have focused on single health outcomes and have not assessed to what extent the association of urbanity with health is explained by population composition or socioeconomic status of the area. Our aim is to investigate associations of urbanity with four different health outcomes (i.e. lung function, metabolic syndrome, depression and anxiety) and to assess whether these associations are independent of residents' characteristics and area socioeconomic status. METHODS: Our study population consisted of 74,733 individuals (42% males, mean age 43.8) who were part of the baseline sample of the LifeLines Cohort Study. Health outcomes were objectively measured with spirometry, a physical examination, laboratory blood analyses, and a psychiatric interview. Using multilevel linear and logistic regression models, associations of urbanity with lung function, and prevalence of metabolic syndrome, major depressive disorder and generalized anxiety disorder were assessed. All models were sequentially adjusted for age, sex, highest education, household equivalent income, smoking, physical activity, and mean neighborhood income. RESULTS: As compared with individuals living in rural areas, those in semi-urban or urban areas had a poorer lung function (ß -1.62, 95% CI -2.07;-1.16), and higher prevalence of major depressive disorder (OR 1.65, 95% CI 1.35;2.00), and generalized anxiety disorder (OR 1.58, 95% CI 1.35;1.84). Prevalence of metabolic syndrome, however, was lower in urban areas (OR 0.51, 95% CI 0.44;0.59). These associations were only partly explained by differences in residents' demographic, socioeconomic and lifestyle characteristics and socioeconomic status of the areas. CONCLUSIONS: Our results suggest a differential health impact of urbanity according to type of disease. Living in an urban environment appears to be beneficial for cardiometabolic health but to have a detrimental impact on respiratory function and mental health. Future research should investigate which underlying mechanisms explain the differential health impact of urbanity.

Changing the obesogenic environment of severe mentally ill residential patients: ELIPS, a cluster randomised study design.

BACKGROUND: Severe mentally ill (SMI) patients have a reduced life expectancy of 13-30 years compared to the general population, largely due to an increased risk of cardiovascular mortality. Unhealthy lifestyle behaviours in SMI patients contribute to this increased risk. The obesogenic living environment of patients in residential facilities may even pose an extra risk. Although several studies have shown positive effects of lifestyle interventions on SMI patients' weight status, studies including residential patients and their obesogenic environment are scarce. This paper describes the Effectiveness of Lifestyle Interventions in PSychiatry trial (ELIPS). The goal of this trial is to improve cardiometabolic health in severe mentally ill residential patients by addressing the obesogenic environment. METHODS/DESIGN: The ELIPS study is a multi-site cluster randomised controlled trial (RCT) based on the principles of a pragmatic RCT. All residential and long-term clinical care teams of two large mental health care organisations in the North of the Netherlands serving SMI patients are invited to participate. The intervention is aimed at team level. Lifestyle coaches first develop a team specific lifestyle plan that tailors the ELIPS goals and protocol and then train teams on how to create a healthy environment and stimulate healthy behaviours in patients. After three months, teams take over the intervention after they have set out goals to achieve in the following nine months. In this phase, adherence to the lifestyle plan and pre-set goals is monitored. Patients in the control arm receive care as usual. Primary outcome measure is waist circumference at three and 12 months after baseline. DISCUSSION: ELIPS is different from previously published lifestyle intervention studies in three ways. First, it follows the principles of a pragmatic design, which enables the examination of effects in everyday practice. Second, by implementing the intervention at team level, we expect lifestyle activities to be maintained when interventionists leave. Last, by targeting the obesogenic environment we create a prerequisite for any sustainable health improvement, as patients can only make healthy choices in a healthy living environment. TRIAL REGISTRATION: Nederlands Trialregister NTR2720 (Dutch Trial Register, www.trialregister.nl). Registered 27 January 2011.

Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study.

AIMS/HYPOTHESIS: Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population. METHODS: We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28-75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes. RESULTS: During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1-Q3) Prx4 level was 0.84 (0.53-1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43-1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05-1.29) in the whole population; by sex, it was 1.31 (1.14-1.50) for men and 1.03 (0.87-1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p = 0.002 for reclassification improvement). CONCLUSIONS/INTERPRETATION: Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.

Effect of obesity intervention programs on adipokines, insulin resistance, lipid profile, and low-grade inflammation in 3- to 5-y-old children.

BACKGROUND: Childhood obesity can cause the development of cardiovascular risk factors. We assessed the effect of a multidisciplinary intervention program on cardiovascular risk factors and compared this effect with a usual-care program in 3- to 5-y-old overweight or obese children. METHODS: Seventy-five children were randomly assigned to a multidisciplinary intervention or a usual-care program. Anthropometry, body composition, and abdominal adipose tissue were assessed at the start and end of a 16-wk program. Concurrently, fasting concentrations of serum lipids, glucose, insulin, HbA1c, leptin, adiponectin, high-sensitive C-reactive protein (hsCRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were determined. RESULTS: In both groups, insulin sensitivity improved, demonstrated by decreased insulin concentrations and a decreased HOMA2-IR. In the multidisciplinary intervention group, there was also a decrease of HbA1c and TNF-α. In the usual-care group, an increase in glucose concentrations was found. Comparing both groups, changes over time were not different, besides trends in the decrease in total cholesterol and TNF-α, in favor of the multidisciplinary intervention group. Combining the results of both groups, a correlation was found between the decrease in body fat percentage (BF%), and both HOMA2-IR and triglyceride (TG) concentrations. CONCLUSION: In 3- to 5-y-old children, both obesity intervention programs improved insulin sensitivity, in parallel with a reduced BF%.

Role of HDL cholesterol and estimates of HDL particle composition in future development of type 2 diabetes in the general population: the PREVEND study.

BACKGROUND AND AIMS: High-density lipoproteins (HDLs) may directly stimulate ß-cell function and glucose metabolism. We determined the relationships of fasting high-density lipoprotein cholesterol (HDL-C), plasma apolipoprotein (apo) A-I and apoA-II, and HDL-C-to-apoA-I and HDL-C-to-apoA-II ratios, as estimates of HDL particle composition, with incident type 2 diabetes mellitus. METHODS: A prospective study was carried out in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort after exclusion of subjects with diabetes at baseline (n = 6820; age, 28-75 years). The association of HDL-related variables with incident type 2 diabetes was determined by multivariate logistic regression analyses. RESULTS: After a median follow-up of 7.7 years, 394 incident cases of type 2 diabetes mellitus were ascertained (5.8%). After adjustment for age, sex, family history of diabetes, body mass index, hypertension, alcohol, and smoking, odd ratios (ORs) for diabetes were 0.55 (95% confidence interval [CI], 0.47-0.64; P < .001), 0.81 (0.71-0.93; P = .002), 0.02 (0.01-0.06; P < .001), and 0.03 (0.01-0.060; P < .001) per 1-SD increase in HDL-C and apoA-I and in the HDL-C-to-apoA-I and the HDL-C-to-apoA-II ratios, respectively. In contrast, apoA-II was not related to incident diabetes (OR = 1.02; 95% CI, 0.90-1.16; P=0.71). The relationships of HDL-C and the ratios of HDL-C to apoA-I and HDL-C to apoA-II remained significant after further adjustment for baseline glucose and triglycerides (OR(HDL) = 0.74 [95% CI, 0.61-0.88], OR(HDL/APO A-I) = 0.14 [0.04-0.44], and OR(HDL/APOA-II) = 0.12 [0.04-0.36]; all P ≤ .001). CONCLUSIONS: Higher HDL-C, as well as higher HDL-C-to-apoA-I and HDL-C-to-apoA-II ratios are strongly and independently related to a lower risk of future type 2 diabetes.

Growth during infancy and childhood, and adiposity at age 16 years: ages 2 to 7 years are pivotal.

OBJECTIVE: To assess the period during infancy and childhood in which growth is most associated with adolescent adiposity and the metabolic syndrome (MS) and whether this differs depending on maternal smoking during pregnancy. STUDY DESIGN: A longitudinal population-based cohort study among 772 girls and 708 boys. RESULTS: Weight gains between ages 2-4 years and ages 4-7 years were most strongly associated with higher body mass index (BMI), sum of skinfold measurements, body fat percentage, and waist circumference at age 16. A one SD increase in weight between ages 2-4 and 4-7 years was associated with increases in outcome measures of +0.82 to +1.47 SDs (all P < .001), and with a less favorable MS score. In children whose mothers smoked during pregnancy, the association of relative weight gain during ages 2-4 years with adolescent BMI was stronger than in children whose mothers did not smoke. For adolescent BMI, the increase was 0.42 SD higher (P = .01). This was similar for the other adiposity measures. CONCLUSIONS: Large relative increases in weight from ages 2 to 7 years are associated with adolescent adiposity and MS. This is more pronounced in adolescents whose mothers smoked during pregnancy.

Prediction models for risk of developing type 2 diabetes: systematic literature search and independent external validation study.

OBJECTIVE: To identify existing prediction models for the risk of development of type 2 diabetes and to externally validate them in a large independent cohort. DATA SOURCES: Systematic search of English, German, and Dutch literature in PubMed until February 2011 to identify prediction models for diabetes. DESIGN: Performance of the models was assessed in terms of discrimination (C statistic) and calibration (calibration plots and Hosmer-Lemeshow test).The validation study was a prospective cohort study, with a case cohort study in a random subcohort. SETTING: Models were applied to the Dutch cohort of the European Prospective Investigation into Cancer and Nutrition cohort study (EPIC-NL). PARTICIPANTS: 38,379 people aged 20-70 with no diabetes at baseline, 2506 of whom made up the random subcohort. OUTCOME MEASURE: Incident type 2 diabetes. RESULTS: The review identified 16 studies containing 25 prediction models. We considered 12 models as basic because they were based on variables that can be assessed non-invasively and 13 models as extended because they additionally included conventional biomarkers such as glucose concentration. During a median follow-up of 10.2 years there were 924 cases in the full EPIC-NL cohort and 79 in the random subcohort. The C statistic for the basic models ranged from 0.74 (95% confidence interval 0.73 to 0.75) to 0.84 (0.82 to 0.85) for risk at 7.5 years. For prediction models including biomarkers the C statistic ranged from 0.81 (0.80 to 0.83) to 0.93 (0.92 to 0.94). Most prediction models overestimated the observed risk of diabetes, particularly at higher observed risks. After adjustment for differences in incidence of diabetes, calibration improved considerably. CONCLUSIONS: Most basic prediction models can identify people at high risk of developing diabetes in a time frame of five to 10 years. Models including biomarkers classified cases slightly better than basic ones. Most models overestimated the actual risk of diabetes. Existing prediction models therefore perform well to identify those at high risk, but cannot sufficiently quantify actual risk of future diabetes.

Parental history of type 2 diabetes and cardiometabolic biomarkers in offspring.

BACKGROUND: Parental history of type 2 diabetes (T2D) is associated with cardiometabolic risk. We aimed to investigate the associations of parental history of T2D with cardiometabolic biomarkers and to subsequently investigate to what extent these putative associations were explained by modifiable factors. MATERIALS AND METHODS: Cross-sectionally, we analysed a random sample of 2001 participants without T2D (20-70 years) from the European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL). Plasma levels of 12 biomarkers - total, HDL and LDL-cholesterol, triglycerides, HbA1c, gamma-glutamyltransferase (GGT), alanine aminotransferase (ALT), asparate aminotransferase (AST), albumin, uric acid, creatinine and high-sensitivity CRP (hs-CRP) - were assessed according to categories of parental history of T2D. RESULTS: In age and sex-adjusted analyses, offspring with parental history of T2D had significantly higher ALT [ß = 0·074; 95% confidence interval (95%CI), 0·023-0·126] and AST levels (ß = 0·033; 95%CI, 0·001 to 0·066) and a trend towards higher HbA1c (ß = 0·011; 95%CI, -0·001 to 0·024) and GGT (ß = 0·049; 95%CI, -0·015 to 0·112) levels. Adjustment for diet, smoking, alcohol intake, physical activity and educational level modestly attenuated the magnitude of these associations, but they remained significant for ALT and borderline significant for AST. After further adjustment for adiposity, additional attenuation was observed, but the association remained significant for ALT. Only maternal history of T2D was associated with higher ALT levels. T2D in both parents was associated with increased levels of all liver enzymes, but the association remained significant for GGT after adjustment for adiposity. Overall, the modifiable factors explained 21·2-45·4% of these associations. The contribution of adiposity was 18·2-38·9%. CONCLUSION: We conclude that parental history of T2D was associated with higher non-fasting levels of liver enzymes in a general population without T2D. Adiposity substantially contributed to these associations. The contribution of diet and lifestyle factors was modest.

External validation of the KORA S4/F4 prediction models for the risk of developing type 2 diabetes in older adults: the PREVEND study.

Recently, prediction models for type 2 diabetes mellitus (T2DM) in older adults (aged ≥55 year) were developed in the KORA S4/F4 study, Augsburg, Germany. We aimed to externally validate the KORA models in a Dutch population. We used data on both older adults (n = 2,050; aged ≥55 year) and total non-diabetic population (n = 6,317; aged 28-75 year) for this validation. We assessed performance of base model (model 1: age, sex, BMI, smoking, parental diabetes and hypertension) and two clinical models: model 1 plus fasting glucose (model 2); and model 2 plus uric acid (model 3). For 7-year risk of T2DM, we calculated C-statistic, Hosmer-Lemeshow χ(2)-statistic, and integrated discrimination improvement (IDI) as measures of discrimination, calibration and reclassification, respectively. After a median follow-up of 7.7 years, 199 (9.7%) and 374 (5.9%) incident cases of T2DM were ascertained in the older and total population, respectively. In the older adults, C-statistic was 0.66 for model 1. This was improved for model 2 and model 3 (C-statistic = 0.81) with significant IDI. In the total population, these respective C-statistics were 0.77, 0.85 and 0.85. All models showed poor calibration (P < 0.001). After adjustment for the intercept and slope of each model, we observed good calibration for most models in both older and total populations. We validated the KORA clinical models for prediction of T2DM in an older Dutch population, with discrimination similar to the development cohort. However, the models need to be corrected for intercept and slope to acquire good calibration for application in a different setting.

Liver function tests and risk prediction of incident type 2 diabetes: evaluation in two independent cohorts.

BACKGROUND: Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking. METHODS AND FINDINGS: We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by~0.020; NRI by~9.0%; P<0.001). In the EPIC-NL case-cohort study, addition to clinical model1 resulted in statistically significant improvement in the overall population (C-statistic = +0.009; P<0.001; NRI = 8.8%; P<0.001), while addition to clinical model 2 yielded marginal improvement limited to men (C-statistic = +0.007; P = 0.06; NRI = 3.3%; P = 0.04). In the PREVEND cohort study, addition to clinical model 1 resulted in significant improvement in the overall population (C-statistic change = 0.008; P = 0.003; NRI = 3.6%; P = 0.03), with largest improvement in men (C-statistic change = 0.013; P = 0.01; NRI = 5.4%; P = 0.04). In PREVEND, improvement compared to clinical model 2 could not be tested because of lack of HbA1c data. CONCLUSIONS: Liver function tests modestly improve prediction for medium-term risk of incident diabetes above basic and extended clinical prediction models, only if no HbA1c is incorporated. If data on HbA1c are available, Liver function tests have little incremental predictive value, although a small benefit may be present in men.

Parental factors affecting the weights of the placenta and the offspring.

AIM: To determine parental, especially paternal factors associated with the weight of the placenta and offspring. METHODS: This population-based birth-cohort study includes 2947 singleton children born from April 2006 to 2007 and living in Drenthe, The Netherlands. Placental weight and birth weight were measured and questionnaires were filled out for this cohort. Associations between parental factors, and the weight of the placenta and the offspring were evaluated using univariate and multivariate linear regression models. RESULTS: Univariate regression revealed that the paternal birth weight and body mass index (BMI) of the father were predictors for placental and birth weight of the offspring. However, they were not independent predictors. Independent predictors for placental weight were the maternal factors of pre-pregnancy BMI, birth weight, and diabetes. The maternal factors of weight gain during pregnancy, birth weight, smoking during pregnancy, and diabetes were independent predictors for birth weight of the offspring. CONCLUSION: Paternal as well as maternal factors influence the weight of the placenta and the offspring.

Vitamin D deficiency: universal risk factor for multifactorial diseases?

In the Western world, the majority of morbidity and mortality are caused by multifactorial diseases. Some risk factors are related to more than one type of disease. These so-called universal risk factors are highly relevant to the population, as reduction of universal risk factors may reduce the prevalence of several types of multifactorial disease simultaneously. Vitamin D deficiency is traditionally seen as an etiological factor in bone disorders such as rickets and osteomalacia. Recent studies also suggest a role for vitamin D deficiency in multifactorial disorders, including progressive renal function loss and cardiovascular disease; it is also a risk factor for frailty. The potentially pleiotropic effects of vitamin D analogues support the hypothesis that vitamin D deficiency is a universal risk factor. Here we review molecular actions of the vitamin D receptor (VDR), to identify mechanisms and pathways for vitamin D deficiency as a universal risk factor. To identify genes directly regulated by the VDR, we searched for genes containing vitamin D response elements (VDREs). A further refinement was made by selecting only VDRE-containing genes with documented modulation by VDR analogues in vivo. Our search yielded a limited number of factors possibly related to pleiotropic effects of vitamin D, including growth factors, hormones, inflammatory factors and factors related to calcium homeostasis. Results from observational, intervention and mechanistic studies indicate that vitamin D is a universal risk factor involved in diverse multifactorial conditions. Further exploration of the multifaceted actions of vitamin D may pave the way for disease-overriding intervention strategies.

Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial.

BACKGROUND: In The Netherlands the largest human Q fever outbreak ever reported in the literature is currently ongoing with more than 2300 notified cases in 2009. Pregnant women are particularly at risk as Q fever during pregnancy may cause maternal and obstetric complications. Since the majority of infected pregnant women are asymptomatic, a screening strategy might be of great value to reduce Q fever related complications. We designed a trial to assess the (cost-)effectiveness of a screening program for Q fever in pregnant women living in risks areas in The Netherlands. METHODS/DESIGN: We will conduct a clustered randomized controlled trial in which primary care midwife centres in Q fever risk areas are randomized to recruit pregnant women for either the control group or the intervention group. In both groups a blood sample is taken around 20 weeks postmenstrual age. In the intervention group, this sample is immediately analyzed by indirect immunofluorescence assay for detection of IgG and IgM antibodies using a sensitive cut-off level of 1:32. In case of an active Q fever infection, antibiotic treatment is recommended and serological follow up is performed. In the control group, serum is frozen for analysis after delivery. The primary endpoint is a maternal (chronic Q fever or reactivation) or obstetric complication (low birth weight, preterm delivery or fetal death) in Q fever positive women. Secondary aims pertain to the course of infection in pregnant women, diagnostic accuracy of laboratory tests used for screening, histo-pathological abnormalities of the placenta of Q fever positive women, side effects of therapy, and costs. The analysis will be according to the intention-to-screen principle, and cost-effectiveness analysis will be performed by comparing the direct and indirect costs between the intervention and control group. DISCUSSION: With this study we aim to provide insight into the balance of risks of undetected and detected Q fever during pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov, protocol record NL30340.042.09.