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Abstract Vitamin D modulates innate and adaptive immunity, the molecular mechanisms of which we aim to understand under human in vivo conditions. Therefore, we designed the study VitDHiD (NCT03537027) as a human investigation, in which 25 healthy individuals were supplemented with a single vitamin D3 bolus (80,000 IU). Transcriptome-wide differential gene expression analysis of peripheral blood mononuclear cells (PBMCs), which were isolated directly before and 24 h after supplementation, identified 452 genes significantly (FDR

Abstract Globally, childhood obesity is on the rise and the effect of objectively measured movement behaviour on body composition remains unclear. Longitudinal and causal mediation relationships of accelerometer-based sedentary time (ST), light physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) with dual-energy X-ray absorptiometry-measured fat mass were examined in 6059 children aged 11 years followed-up until age 24 years from the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort. Over 13-year follow-up, each minute/day of ST was associated with 1.3 g increase in fat mass. However, each minute/day of LPA was associated with 3.6 g decrease in fat mass and each minute/day of MVPA was associated with 1.3 g decrease in fat mass. Persistently accruing ≥60 min/day of MVPA was associated with 2.8 g decrease in fat mass per each minute/day of MVPA, partly mediated by decrease insulin and low-density lipoprotein cholesterol. LPA elicited similar and potentially stronger fat mass-lowering effect than MVPA and thus may be targeted in obesity and ST prevention in children and adolescents, who are unable or unwilling to exercise.

Abstract Aims We aim to evaluate the association of frailty and high body mass index with risk of incident heart failure. Methods and results From the Kuopio Ischaemic Heart Disease Risk Factor Study, 408 women and 369 men, aged 61–74 years were included in this study. Frailty was ascertained with the presence of 3–5 and prefrailty 1–2 of the following criteria: weight loss (highest 20% over 7 years), self‐reported tiredness, weakness (measured by handgrip strength), slow walking speed (walking pace), and low physical activity (lowest 20%). At the baseline, participants were allocated to frail (n = 36), prefrail (n = 340), and robust (n = 441). HF incidents were obtained by record linkages from the national hospitalization registry in Finland up to 31 December 2019. Multivariate Cox proportional hazards regression estimated the hazard ratio (HR) of incident events, adjusted for potential confounders. Two hundred one HF events were recorded (111 in women and 90 in men) during the 14.2 years follow‐up. After adjustment for the age and sex, the risk of HF events was higher among prefrail (HR 1.42, 95% CI 1.08 to 1.79, P = 0.02) and frail (HR 3.39, 95% CI 1.89 to 4.79, P ≤ 0.001) compared with the robust group. After adjusting for multiple confounders result remained significant for HF indecent in prefrail [1.46 (HR 1.46, 95% CI 1.09 to 1.95, P = 0.01] and frail (HR 3.33, 95% CI 1.86 to 5.70, P ≤ 0.001). In the sensitivity analysis, significant interaction between high BMI (≥25 kg/m2) and frailty was observed (P for interaction = 0.02). The association of frailty [multivariate‐adjusted HR: 2.88 (1.56 to 5.33), P ≤ 0.001)] and prefrailty [multivariate‐adjusted HR: 1.40 (1.08 to 1.91), P = 0.03)] with risk of HF indecent was more pronounced in those with high BMI. Conclusions Frailty is highly common in older age, and our results indicated the high risk of HF incident in frail and prefrail groups. While frailty is clinically recognized by weight loss phenotype, our finding showed that frailly and high BMI can coexist and worsen the risk of HF incidence. Further research is warranted to substantiate these results in large studies and clinical settings.

Objective The purpose of this study was to discover how considering multiplicative, additive, and interactive effects modifies results of a prospective cohort study on coronary heart disease (CHD) incidence and its main risk factors.Material and methods The Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study provided the study material, 2682 Eastern Finnish middle-aged men, followed since the 1980s. We applied multiplicative and additive survival models together with different statistical metrics and confidence intervals for risk ratios and risk differences to estimate the nature of associations.Results The mean (SD) follow-up time among men who were free of CHD at baseline (n = 1958) was 21.4 (10.4) years, and 717 (37%) of them had the disease and 301 (15%) died for CHD before the end of follow-up. All tested non-modifiable and modifiable risk factors statistically significantly predicted CHD incidence. We detected three interactions: circulating low-density lipoprotein cholesterol (LDL-C) × age, obesity × age, and obesity × smoking of which LDL-C × age was the most evident one. High LDL-C increased the risk of CHD more among men younger than 50 [risk ratio (RR) 2.10] than those older than 50 (RR 1.22). LDL-C status was the only additive covariate. The additive effect of high LDL-C increased almost linearly up to 18 years and then reached a plateau. The simple multiplicative survival model stressed glycemic status as the strongest modifiable risk factor for developing CHD [hazard ratio (HR) for diabetes vs. normoglycemia was 2.69], whereas the model considering interactions and time dependence emphasised the role of LDL-C status (HR for high LDL-C vs. lower than borderline was 4.43). Age was the strongest non-modifiable predictor.Conclusions Including covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses and ease to define the order of importance across CHD risk factors. KEY MESSAGESIncluding covariate interactions and time dependence in survival models potentially refine results of epidemiological analyses on coronary heart disease.Including covariate interactions and time dependence in survival models potentially ease to define the order of importance across coronary heart disease risk factors.

Abstract Purpose Recent studies have suggested that higher postmenopausal follicle stimulating hormone (FSH) may be associated with lower risk of diabetes. However, relatively little is known about postmenopausal FSH levels, including the level of variation between women and whether reproductive factors are associated with this variation. Methods We assessed the relationship of multiple reproductive factors with FSH levels among 588 postmenopausal women in the Kuopio Ischaemic Heart Disease Risk Factor Study. Participants were aged 53 to 73 years and not using hormone therapy at study enrollment (1998–2001) when reproductive factors were assessed and FSH was measured. Results After adjustment for age, menopause timing, sex steroid levels, adiposity and behavioral factors, we observed numbers of pregnancies and age at first birth were each inversely associated with FSH levels. For example, women with ≥ 3 births and an age at first birth ≥ 25 years had mean FSH levels that were 7.8 IU/L lower than those of women with 1–2 births and an age at first birth ≤ 24 years (P = 0.003). Number of miscarriages was inversely associated with FSH levels (-2.7 IU/L per miscarriage; P = 0.02). Women reporting 4 or more years of past hormone therapy use had significantly higher mean FSH levels than women who had never used hormone therapy (P for trend = 0.006). Conclusion Multiple reproductive factors were associated with postmenopausal FSH, independent of estradiol, adiposity and other confounders. These findings warrant replication and further exploration of potential underlying mechanism.

Abstract Background Lower urinary sodium concentrations (UNa) may be a biomarker for poor prognosis in chronic heart failure (HF). However, no data exist to determine its prognostic association over the long-term. We investigated whether UNa predicted major adverse coronary events (MACE) and all-cause mortality over 28–33 years. Methods One hundred and eighty men with chronic HF from the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) were included. Baseline data was collected between 1984 and 1989. MACE and all-cause outcomes were obtained using hospital linkage data (1984–2017) with a follow-up of 28–33 years. Cox proportional hazards models were generated using 24-h UNa tertiles at baseline (1 ≤ 173 mmol/day; 2 = 173-229 mmol/day; 3 = 230-491 mmol/day) as a predictor of time-to-MACE outcomes, adjusted for relevant covariates. Results Overall, 63% and 83% of participants (n = 114 and n = 150) had a MACE event (median 10 years) and all-cause mortality event (median 19 years), respectively. On multivariable Cox Model, relative to the lowest UNa tertile, no significant difference was noted in MACE outcome for individuals in tertiles 2 and 3 with events rates of 28% (HR:0.72; 95% CI: 0.46–1.12) and 21% (HR 0.79; 95% CI: 0.5–1.25) respectively.. Relative to the lowest UNa tertile, those in tertile 2 and 3 were 39% (HR: 0.61; 95% CIs: 0.41, 0.91) and 10% (HR: 0.90; 95% CIs: 0.62, 1.33) less likely to experience to experience all-cause mortality. The multivariable Cox model had acceptable prediction precision (Harrell's C concordance measure 0.72). Conclusion UNa was a significant predictor of all-cause mortality but not MACE outcomes over 28–33 years with 173–229 mmol/day appearing to be the optimal level. UNa may represent an emerging long-term prognostic biomarker that warrants further investigation.

Background: Little is known about the role of economic recessions in the risk of cancer. Therefore, we evaluated the impact of the severe economic recession in Finland from 1991–1994 on the incidence of all cancers and cancer subtypes among a middle-age and older population. Methods: From the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), a population-based sample of 1,620 women and men aged 53–73 years were examined from 1998–2001. The cancer-free participants completed a questionnaire on the possible impact of the 1990s recession in Finland on their lives. Incident cases of cancer were obtained through record linkage with the Finnish Cancer Registry. Cox proportional hazards regression was used to estimate hazard ratios (HR) of incident cancer events after adjusting for possible confounders. Results: A total of 1,096 cancer-free participants had experienced socioeconomic hardships due to the recession at the baseline. During 20 years of follow-up, 473 participants developed cancer. After adjustment for age, baseline socioeconomic position, and lifestyle factors, the risk of all cancers was 32% higher among men who experienced socioeconomic hardships compared to those who did not (HR 1.32; 95% confidence interval [CI], 1.00–1.74, P = 0.05). Prostate-genital cancer was 71% higher among men with hardships (n = 103, HR 1.71; 95% CI, 1.06–2.74, P = 0.02). No association was observed between socioeconomic hardships and subsequent risk of total or any subtype of cancer among women. Conclusion: The 1990s economic recession was associated with increased risk of all cancers, especially prostate-genital cancer among Finnish middle-age and older men, but no association with cancer was observed in women.

Background The association between common carotid artery intima‐media thickness (CCA‐IMT) and incident carotid plaque has not been characterized fully. We therefore aimed to precisely quantify the relationship between CCA‐IMT and carotid plaque development. Methods and Results We undertook an individual participant data meta‐analysis of 20 prospective studies from the Proof‐ATHERO (Prospective Studies of Atherosclerosis) consortium that recorded baseline CCA‐IMT and incident carotid plaque involving 21 494 individuals without a history of cardiovascular disease and without preexisting carotid plaque at baseline. Mean baseline age was 56 years (SD, 9 years), 55% were women, and mean baseline CCA‐IMT was 0.71 mm (SD, 0.17 mm). Over a median follow‐up of 5.9 years (5th–95th percentile, 1.9–19.0 years), 8278 individuals developed first‐ever carotid plaque. We combined study‐specific odds ratios (ORs) for incident carotid plaque using random‐effects meta‐analysis. Baseline CCA‐IMT was approximately log‐linearly associated with the odds of developing carotid plaque. The age‐, sex‐, and trial arm–adjusted OR for carotid plaque per SD higher baseline CCA‐IMT was 1.40 (95% CI, 1.31–1.50; I2=63.9%). The corresponding OR that was further adjusted for ethnicity, smoking, diabetes, body mass index, systolic blood pressure, low‐ and high‐density lipoprotein cholesterol, and lipid‐lowering and antihypertensive medication was 1.34 (95% CI, 1.24–1.45; I2=59.4%; 14 studies; 16 297 participants; 6381 incident plaques). We observed no significant effect modification across clinically relevant subgroups. Sensitivity analysis restricted to studies defining plaque as focal thickening yielded a comparable OR (1.38 [95% CI, 1.29–1.47]; I2=57.1%; 14 studies; 17 352 participants; 6991 incident plaques). Conclusions Our large‐scale individual participant data meta‐analysis demonstrated that CCA‐IMT is associated with the long‐term risk of developing first‐ever carotid plaque, independent of traditional cardiovascular risk factors.

Abstract Background Iron stores, estimated as ferritin levels, and type 2 diabetes (T2D) have been associated previously, while findings regarding coronary heart disease (CHD) and cerebrovascular disease (CEVD) are still inconclusive. No study has focused on simultaneous evaluation of associations between iron stores and the above cardiometabolic diseases (CMD) in the same population. We aim to evaluate the association between serum ferritin and risk of T2D, CHD and CEVD in Scottish population over a wide range of ferritin levels. Methods Longitudinal study in 6,497 participants of the 1995 and 1998 Scottish health surveys, who were followed-up until 2011. Cox regression models were conducted adjusting for age, sex/menopausal status, fibrinogen, GGT levels, smoking, alcohol consumption, total cholesterol, HDL-cholesterol, blood pressure, and BMI. Ferritin was used as continuous (sex/menopausal status-specific Z score) and categorical variable (sex/menopausal status-specific quartiles, quintiles and sextiles). Results During follow-up, 4.9% of the participants developed T2D, 5.3% CHD, and 2.3% CEVD. By using ferritin quartiles, serum ferritin was positively associated with T2D, CHD and CEVD but only the association with T2D remained after adjustment for covariates [Quartile 4 v. 1: adjusted HR 95% CI 1.59 (1.10–2.34); P = 0.006]. When ferritin sextiles were used (6 v. 1), the ferritin-CEVD association became slightly stronger and significant [adjusted HR 95% CI 2.08 (1.09–3.94); P = 0.024]. Conclusions Iron stores relate differently to each CMD. Serum ferritin levels were positively and independently associated with incident T2D, and with incident CEVD if higher cut-off points for high ferritin levels were considered.

Purpose: To estimate the maximum mass-specific oxygen uptake (VO2max) from the ratio of the heart rate at maximal exercise (HRmax) to heart rate at rest (HRrest) in middle-aged men. VO2max is an essential measure of cardiorespiratory fitness, but it is difficult to utilize in clinical practice. The proportionality factor HRmax to HRrest is known to approximate 15 in young welltrained adults. Presumably, the same value is inaccurate for middle-aged men. Materials and Methods: Six-hundred thirty-four men belonging to the Kuopio Ischaemic Heart Disease Risk Factor Study. Their mean age, body mass index (BMI), the daily total physical activity (TPA), VO2max, HRmax, and HRrest were: 49.4±6.4 years, 26.3±3.2 kg/m2, 48.5±10.1 metabolic equivalent hours per day, 33.7±7.6 mL/min/kg, 170.1±15.4 beats/min, and 63.3±10.8 beats/min. They included never-smokers 38%, former smokers 29%, and current smokers 33%. Results: The proportionality factor HRmax to HRrest in around 50-year-old men approximated 12. One year in age, one step change in BMI (normal weight, overweight, obese), smoking status (never, former, current), and TPA (moderately active, active, highly active) reduced the proportionality factor by 0.1, 0.6, 0.4, and 0.1, respectively. The proportionality factor in obese or current smoking middle-aged men was one point lower compared to normal weight or never-smoking peers. This corresponds to approximately 10 years in chronological age. Conclusions: In around 50-year-old men with no cardiovascular diseases, bronchial asthma, or cancer, the HRmax to HRrest ratio should be multiplied by approximately 12 to estimate VO2max. BMI and smoking status can be considered in calculations to improve accuracy.

Background The major risk factors for atherosclerotic cardiovascular disease differ by race or ethnicity but have largely been defined using populations of European ancestry. Despite the rising prevalence of cardiovascular disease in Africa there are few related data from African populations. Therefore, we compared the association of established cardiovascular risk factors with carotid‐intima media thickness (CIMT), a subclinical marker of atherosclerosis, between African, African American, Asian, European, and Hispanic populations. Methods and Results Cross‐sectional analyses of 34 025 men and women drawn from 15 cohorts in Africa, Asia, Europe, and North America were undertaken. Classical cardiovascular risk factors were assessed and CIMT measured using B‐mode ultrasound. Ethnic differences in the association of established cardiovascular risk factors with CIMT were determined using a 1‐stage individual participant data meta‐analysis with beta coefficients expressed as a percentage using the White population as the reference group. CIMT adjusted for risk factors was the greatest among African American populations followed by Asian, European, and Hispanic populations with African populations having the lowest mean CIMT. In all racial or ethnic groups, men had higher CIMT levels compared with women. Age, sex, body mass index, and systolic blood pressure had a significant positive association with CIMT in all races and ethnicities at varying magnitudes. When compared with European populations, the association of age, sex, and systolic blood pressure with CIMT was weaker in all races and ethnicities. Smoking (beta coefficient, 0.39; 95% CI, 0.09–0.70), body mass index (beta coefficient, 0.05; 95% CI, 0.01–0.08) and glucose (beta coefficient, 0.13; 95% CI, 0.06–0.19) had the strongest positive association with CIMT in the Asian population when compared with all other racial and ethnic groups. High‐density lipoprotein‐cholesterol had significant protective effects in African American (beta coefficient, −0.31; 95% CI, −0.42 to −0.21) and African (beta coefficient, −0.26; 95% CI, −0.31 to −0.19) populations only. Conclusions The strength of association between established cardiovascular risk factors and CIMT differed across the racial or ethnic groups and may be due to lifestyle risk factors and genetics. These differences have implications for race‐ ethnicity‐specific primary prevention strategies and also give insights into the differential contribution of risk factors to the pathogenesis of cardiovascular disease. The greatest burden of subclinical atherosclerosis in African American individuals warrants further investigations.

AbstractBackground We carried out this study to demonstrate the effects of outcome sensitivity, participant exclusions, and covariate manipulations on results of the epidemiological analysis of coronary heart disease (CHD) and its behaviour-related risk factors.Material and methods Our study population consisted of 1592 54-year-old men, who participated in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) Study. We used the Cox proportional-hazards model to predict the hazard of CHD and applied different sets of outcomes concerning outcome sensitivity and data preprocessing procedures regarding participant exclusions and covariate manipulations.Results The mean follow-up time was 23 years, and 730 men received the CHD diagnosis. Cox regressions based on data with no participant exclusions most often discovered statistically significant associations. Loose inclusion criteria for study participants with any CVD during the follow-up and strict exclusion criteria for participants with no CVD were best in discovering the associations between risk factors and CHD. Outcome sensitivity affected the associations, whereas the covariate type, continuous or categorical, did not.Conclusions This study suggests that excluding study participants who are not disease-free at baseline is probably unnecessary for epidemiological analyses. Epidemiological research reports should present results based on no data exclusions together with results based on reasoned exclusions.

BackgroundLong-term development of psychiatric disorders and alcohol-related diseases after economic recessions is insufficiently studied. We investigated the overall impact of the economic recession between 1991 and 1994 in Finland on the long-term incidence of psychiatric and alcohol-related diseases.MethodsA population-based sample of 1,774 women and men aged 53–73 years were examined between 1998 and 2001 from the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD). Participants completed comprehensive questionnaires on the possible impact of the 1990s recession in Finland on their lives. They were followed-up until 2018. Cox proportional hazards regression was used to estimate hazard ratios (HR) of new incident psychiatric and alcohol-related disorders during the 20-years follow-up after linkage to the National Hospital Registry. Logistic regression was used to estimate odds ratios (OR) of psychiatric disorders at baseline.ResultsAt baseline, 93 participants had psychiatric disorders. During 20-years follow-up, 138 new psychiatric disorders and 45 alcohol-related diseases were developed. The covariate-adjusted risk of psychiatric disorders was over twice higher among men who experienced recession-induced hardships compared to those who did not (HR = 2.20, 95%CI = 1.04–4.70, p = 0.04). The risk of alcohol-related diseases was more than four times higher among men with hardships (HR = 4.44, 95%CI = 1.04–18.90, p = 0.04). No such associations were observed among women. No association was observed between recession-induced hardships and having psychiatric disorders at baseline in both genders (multivariate-adjusted p = 0.63 for women, multivariate-adjusted p = 0.36 for men).ConclusionLong-term risk of psychiatric disorders and alcohol-related diseases was increased after the 1990s economic recession in Finland, but only among middle-age and older men.

OBJECTIVES Renal hyperfiltration (RHF) and fatty liver are separately associated with adverse health outcomes. In this study, we investigated the mortality hazard of coexisting RHF and fatty liver. METHODS Middle-aged men from the Kuopio Ischaemic Disease Risk Factor Study (n=1,552) were followed up for a median of 29 years. Associations among RHF, fatty liver index (FLI) score, age, body mass index, smoking status, alcohol consumption, and hypertension status were assessed using logistic regression. Cox proportional hazards models were used to determine the hazard ratios (HRs) for all-cause and cardiovascular disease (CVD) mortality with respect to RHF and fatty liver. RESULTS Of the men, 5% had RHF (n=73), whereas a majority had fatty liver (n=848). RHF was associated specifically with smoking, and fatty liver was associated specifically with overweight. The all-cause mortality hazard was highest (HR, 1.96; 95% confidence interval [CI], 1.27 to 3.01) among men with RHF and fatty liver (n=33). Among men with RHF but normal FLI (n=40), the HR of all-cause mortality was 1.67 (95% CI, 1.15 to 2.42). Among men with fatty liver but a normal estimated glomerular filtration rate (n=527), the HR of all-cause mortality was 1.35 (95% CI, 1.09 to 1.66). CVD mortality hazard was associated with RHF, but not fatty liver. We detected no interaction effect between RHF and fatty liver for all-cause (synergy index, 0.74; 95% CI, 0.21 to 2.67) or CVD (synergy index, 0.94; 95% CI, 0.34 to 2.60) mortality. CONCLUSIONS RHF and fatty liver are independently associated with all-cause and CVD mortality

BackgroundDe novo lipogenesis (DNL) is the primary metabolic pathway synthesizing fatty acids from carbohydrates, protein, or alcohol. Our aim was to examine associations of in vivo levels of selected fatty acids (16:0, 16:1n7, 18:0, 18:1n9) in DNL with incidence of type 2 diabetes (T2D).Methods and findingsSeventeen cohorts from 12 countries (7 from Europe, 7 from the United States, 1 from Australia, 1 from Taiwan; baseline years = 1970-1973 to 2006-2010) conducted harmonized individual-level analyses of associations of DNL-related fatty acids with incident T2D. In total, we evaluated 65,225 participants (mean ages = 52.3-75.5 years; % women = 20.4%-62.3% in 12 cohorts recruiting both sexes) and 15,383 incident cases of T2D over the 9-year follow-up on average. Cohort-specific association of each of 16:0, 16:1n7, 18:0, and 18:1n9 with incident T2D was estimated, adjusted for demographic factors, socioeconomic characteristics, alcohol, smoking, physical activity, dyslipidemia, hypertension, menopausal status, and adiposity. Cohort-specific associations were meta-analyzed with an inverse-variance-weighted approach. Each of the 4 fatty acids positively related to incident T2D. Relative risks (RRs) per cohort-specific range between midpoints of the top and bottom quintiles of fatty acid concentrations were 1.53 (1.41-1.66; p < 0.001) for 16:0, 1.40 (1.33-1.48; p < 0.001) for 16:1n-7, 1.14 (1.05-1.22; p = 0.001) for 18:0, and 1.16 (1.07-1.25; p < 0.001) for 18:1n9. Heterogeneity was seen across cohorts (I2 = 51.1%-73.1% for each fatty acid) but not explained by lipid fractions and global geographical regions. Further adjusted for triglycerides (and 16:0 when appropriate) to evaluate associations independent of overall DNL, the associations remained significant for 16:0, 16:1n7, and 18:0 but were attenuated for 18:1n9 (RR = 1.03, 95% confidence interval (CI) = 0.94-1.13). These findings had limitations in potential reverse causation and residual confounding by imprecisely measured or unmeasured factors.ConclusionsConcentrations of fatty acids in the DNL were positively associated with T2D incidence. Our findings support further work to investigate a possible role of DNL and individual fatty acids in the development of T2D.

Abstract Background A Finnish joint research effort Kuopio Birth Cohort (KuBiCo) seeks to evaluate the effects of genetics, epigenetics and different risk factors (medication, nutrition, lifestyle factors and environmental aspects) during pregnancy on the somatic and psychological health status of the mother and the child. Methods KuBiCo will ultimately include information on 10,000 mother-child pairs who have given their informed consent to participate in this cohort. Identification of foetal health risk factors that can potentially later manifest as disease requires a repository of relevant biological samples and a flexible open up-to-date data handling system to register, store and analyse biological, clinical and questionnaire-based data. KuBiCo includes coded questionnaire-based maternal background data gathered before, during and after the pregnancy and bio-banking of maternal and foetal samples that will be stored in deep freezers. Data from the questionnaires and biological samples will be collected into one electronic database. KuBiCo consists of several work packages which are complementary to each other: Maternal, foetal and placental metabolism and omics; Paediatrics; Mental wellbeing; Prenatal period and delivery; Analgesics and anaesthetics during peripartum period; Environmental effects; Nutrition; and Research ethics. Discussion This report describes the set-up of the KuBiCo and descriptive analysis from 3532 parturients on response frequencies and feedback to KuBiCo questionnaires gathered from June 2012 to April 2016. Additionally, we describe basic demographic data of the participants (n = 1172). Based on the comparison of demographic data between official national statistics and our descriptive analysis, KuBiCo represents a cross-section of Finnish pregnant women.

Abstract Background The redundancy of information is becoming a critical issue for epidemiologists. High-dimensional datasets require new effective variable selection methods to be developed. This study implements an advanced evolutionary variable selection method which is applied for cardiovascular predictive modeling. The epidemiological follow-up study KIHD (Kuopio Ischemic Heart Disease Risk Factor Study) was used to compare the designed variable selection method based on an evolutionary search with conventional stepwise selection. The sample contains in total 433 predictor variables and a response variable indicating incidents of cardiovascular diseases for 1465 study subjects. Results The effectiveness of variable selection methods was investigated in combination with two models: Generalized Linear Logistic Regression and Support Vector Machine. We managed to decrease the number of variables from 433 to 38 and save the predictive ability of the models used. Their performance was evaluated with an F-score metric. At most, we gained 65.6% and 67.4% of the F-score before and after variable selection respectively. All the results were averaged over 5-folds of a cross-validation procedure. Conclusions The presented evolutionary variable selection method allows a reduced set of variables to be chosen which are relevant to predicting cardiovascular diseases. A reference list of the most meaningful variables is introduced to be used as a basis for new epidemiological studies. In general, the multicollinearity of variables enables different combinations of predictors to be used and the same performance of models to be attained.

Post-analysis of predictive models fosters their application in practice, as domain experts want to understand the logic behind them. In epidemiology, methods explaining sophisticated models facilitate the usage of up-to-date tools, especially in the high-dimensional predictor space. Investigating how model performance varies for subjects with different conditions is one of the important parts of post-analysis. This paper presents a model-independent approach for post-analysis, aiming to reveal those subjects’ conditions that lead to low or high model performance, compared to the average level on the whole sample. Conditions of interest are presented in the form of rules generated by a multi-objective evolutionary algorithm (MOGA). In this study, Lasso logistic regression (LLR) was trained to predict cardiovascular death by 2016 using the data from the 1984–1989 examination within the Kuopio Ischemic Heart Disease Risk Factor Study (KIHD), which contained 2682 subjects and 950 preselected predictors. After 50 independent runs of five-fold cross-validation, the model performance collected for each subject was used to generate rules describing “easy” and “difficult” cases. LLR with 61 selected predictors, on average, achieved 72.53% accuracy on the whole sample. However, during post-analysis, three categories of subjects were discovered: “Easy” cases with an LLR accuracy of 95.84%, “difficult” cases with an LLR accuracy of 48.11%, and the remaining cases with an LLR accuracy of 71.00%. Moreover, the rule analysis showed that medication was one of the main confusing factors that led to lower model performance. The proposed approach provides insightful information about subjects’ conditions that complicate predictive modeling.

ObjectiveFatty liver disease (FLD) has been associated with extrahepatic morbidity outcomes. However, reports on the association of FLD, assessed using fatty liver index (FLI), with mortality outcomes have been inconsistent. Our objective was to examine the effect of metabolic factors (blood pressure, insulin, fasting glucose, lipoproteins) on the associations of FLI with mortality outcomes among middle-aged men.Study designProspective cohort study.MethodsOur subjects were 1893 men at baseline from 1984 to 1989 in the Kuopio Ischaemic Heart Disease Risk Factor Study cohort. Multivariable Cox regression models were used to analyse the association of baseline FLI, with the HRs for all-cause, disease, cardiovascular, non-cardiovascular and cancer mortality outcomes.ResultsThe mean FLI in the FLI categories were 16.2 in the low and reference category (FLI

[This corrects the article DOI: 10.1371/journal.pone.0191172.].

AIMS:Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk. METHODS AND RESULTS:From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies. In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95-1.02) in group A, 0.98 (0.93-1.04) in group B, and 0.95 (0.89-1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07-1.23) in group A, 1.13 (1.05-1.22) in group B, and 1.12 (1.05-1.20) in group C. CONCLUSIONS:We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.

BACKGROUND:The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation. METHODS:Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group. RESULTS:Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women. CONCLUSION:Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.

Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels. Network and self-organizing map analysis of these datasets together with that of the other 24 parameters was followed by relevance calculations and identified changes in parathyroid hormone serum levels and the expression of the newly selected genes STS, BCL6, ITGAM, LRRC25, LPGAT1 and TREM1 as well as of the previously reported genes DUSP10 and CD14 as the most relevant parameters for describing vitamin D responsiveness in vivo. Moreover, parameter relevance ranking allowed the segregation of study subjects into high and low responders. Due to the long intervention period the vitamin D response was not too prominent on the level of transcriptional activation. Therefore, we performed in the separate VitDbol trial a short-term but high dose stimulation with a vitamin D3 bolus. In PBMCs of VitDbol subjects we observed direct transcriptional effects on the selected VDR target genes, such as an up to 2.1-fold increase already one day after supplementation onset. In conclusion, both long-term and short-term vitamin D3 supplementation studies allow monitoring the vitamin D responsiveness of human individuals and represent new types of human in vivo vitamin D3 investigations.

Epidemiological evidence suggests a role for vitamin D in type 2 diabetes prevention. We investigated the effects of vitamin D3 supplementation on glucose metabolism and inflammation in subjects with prediabetes. A 5-month randomized, double-blind, placebo-controlled intervention with three arms (placebo, 40 μg/d, or 80 μg/d vitamin D3) was carried out among sixty-eight overweight (BMI 25–35) and aging (≥60 years) subjects from Finland, with serum 25-hydroxyvitamin D3 [25(OH)D3] < 75 nmol/L and either impaired fasting glucose or impaired glucose tolerance. Analyses included 66 subjects who completed the trial. Glucose metabolism was evaluated by fasting and 2-hour oral glucose tolerance test-derived indices and glycated hemoglobin. Inflammation was evaluated by high-sensitive C-reactive protein and five cytokines. Although a dose-dependent increase in serum 25(OH)D3 over the supplementation period was observed (P trend < 0.001), there were no other statistically significant differences in changes in the 13 glucose homeostasis indicators between the study groups other than increase in the 120 min glucose concentration (P trend = 0.021) and a decreasing trend both in 30 min plasma insulin (P trend = 0.030) and glycated hemoglobin (P trend = 0.024) concentrations. A borderline statistically significant decreasing trend in interleukin-1 receptor antagonist concentration was observed (P = 0.070). Vitamin D3 supplementation does not improve glucose metabolism in ageing subjects with prediabetes but may have modest anti-inflammatory effects.

BACKGROUND:Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES:We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES:Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA:Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS:We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS:Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS:Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk.

Vitamin D deficiency has been associated with an increased risk of developing a number of diseases. Here we investigated samples from 71 pre-diabetic individuals of the VitDmet study, a 5-month high dose vitamin D3 intervention trial during Finnish winter, for their changes in serum 25-hydroxyvitamin D3 (25(OH)D3) concentrations and the expression of primary vitamin D target genes in peripheral blood mononuclear cells and adipose tissue. A negative correlation between serum concentrations of parathyroid hormone and 25(OH)D3 suggested an overall normal physiological vitamin D response among the participants. The genes CD14 and thrombomodulin (THBD) are up-regulated primary vitamin D targets and showed to be suitable gene expression markers for vitamin D signaling in both primary tissues. However, in a ranking of the samples concerning their expected response to vitamin D only the top half showed a positive correlation between the changes of CD14 or THBD mRNA and serum 25(OH)D3 concentrations. Interestingly, this categorization allows unmasking a negative correlation between changes in serum concentrations of 25(OH)D3 and the inflammation marker interleukin 6. We propose the genes CD14 and THBD as transcriptomic biomarkers, from which the effects of a vitamin D3 supplementation can be evaluated. These biomarkers allow the classification of subjects into those, who might benefit from a vitamin D3 supplementation, and others who do not.

ObjectivesFish consumption has been associated with reduced risk of cardiovascular diseases (CVD), especially sudden cardiac death (SCD). Fish is the major source of long-chain n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid and docosahexaenoic acid. It is also a major source of methylmercury, which was associated with increased risk of CVD in this study population. Impact of interaction between long-chain n-3 PUFA and methylmercury on the SCD risk is unknown.MethodsA total of 1857 men from the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor study, aged 42-60 years and free of CVD at baseline in 1984-1989, were studied. Serum long-chain n-3 PUFA was used as the marker for long-chain n-3 PUFA intake and hair mercury as the marker for mercury exposure.ResultsDuring the mean follow-up of 20.1 years, 91 SCD events occurred. In the multivariate Cox proportional hazards regression models, serum long-chain n-3 PUFA concentration was not associated with the risk of SCD until hair mercury was accounted for; then the hazard ratio (HR) in the highest vs. lowest tertile was 0.54 [95% confidence interval (CI) 0.32 to 0.91, p for trend = 0.046]. When the analyses were stratified by hair mercury content, among those with lower hair mercury, each 0.5 percentage unit increase in the serum long-chain n-3 PUFA was associated with HR of 0.77 (95% CI 0.64 to 0.93), whereas no association was seen among those with higher hair mercury (p for interaction = 0.01). Among the individual long-chain n-3 PUFA, docosahexaenoic acid was most strongly associated with the risk.ConclusionHigh exposure to mercury may reduce the benefits of long-chain n-3 PUFA on SCD.

Prenatal life exposures, potentially manifested as altered birth size, may influence the later risk of major chronic diseases through direct biologic effects on disease processes, but also by modifying adult behaviors such as physical activity that may influence later disease risk.We investigated the association between birth weight and leisure time physical activity (LTPA) in 43,482 adolescents and adults from 13 Nordic cohorts. Random effects meta-analyses were performed on categorical estimates from cohort-, age-, sex- and birth weight specific analyses. Birth weight showed a reverse U-shaped association with later LTPA; within the range of normal weight the association was negligible but weights below and above this range were associated with a lower probability of undertaking LTPA. Compared with the reference category (3.26-3.75 kg), the birth weight categories of 1.26-1.75, 1.76-2.25, 2.26-2.75, and 4.76-5.25 kg, had odds ratios of 0.67 (95% confidence interval: 0.47, 0.94), 0.72 (0.59, 0.88), 0.89 (0.79, 0.99), and 0.65 (0.50, 0.86), respectively. The shape and strength of the birth weight-LTPA association was virtually independent of sex, age, gestational age, educational level, concurrent body mass index, and smoking.The association between birth weight and undertaking LTPA is very weak within the normal birth weight range, but both low and high birth weights are associated with a lower probability of undertaking LTPA, which hence may be a mediator between prenatal influences and later disease risk.

The role of circulating levels of total homocysteine tHcy in the development of coronary heart disease (CHD) is still under debate. One reason for conflicting results between previous studies on homocysteine and heart diseases could be consequence of different interactions between homocysteine and genes in different study populations. Many genetic factors play a role in folate-homocysteine metabolism, like functional polymorphism (Val108Met) in the Catechol-O-methyltransferase (COMT) gene.Our aim was to examine the role of COMT Val158Met polymorphism and interaction of this polymorphism with serum tHcy and folate concentration on the risk of acute coronary and events in middle-aged men from eastern Finland. A population-based prospective cohort of 792 men aged 46-64 years was examined as part of the Kuopio Ischaemic Heart Disease Risk Factor Study. During an average follow-up of 9.3 years, there were 69 acute coronary events in men with no previous history of CHD. When comparing the COMT low activity genotype with the others, we found an age and examination year adjusted hazard rate ratio (HRR) of 1.73 (95% confidence interval (CI), 1.07-2.79), and an age, examination year, serum LDL and HDL cholesterol, and triglyceride concentration, systolic blood pressure and smoking adjusted HRR of 1.77 (95% CI, 1.05-2.77). Although serum tHcy concentration was not statistically significantly associated with acute coronary events (HRR for the highest third versus others 1.52, 95% CI, 0.93-2.49), subjects with both high serum tHcy and the COMT low activity genotype had an additionally increased adjusted risk of HRR 2.94 (95% CI 1.50-5.76) as compared with other men.This prospective cohort study suggests that the functional COMT Val158Met polymorphism is associated with increased risk of acute coronary events and it may interact with high serum tHcy levels.

BACKGROUND: The role of coffee intake as a risk factor for coronary heart disease (CHD) has been debated for decades. We examined whether the relationship between coffee intake and incidence of CHD events is dependent on the metabolism of circulating catecholamines, as determined by functional polymorphism of the catechol-O-methyltransferase (COMT) gene. METHODOLOGY/PRINCIPAL FINDINGS: In a cohort of 773 men who were 42 to 60 years old and free of symptomatic CHD at baseline in 1984-89, 78 participants experienced an acute coronary event during an average follow-up of 13 years. In logistic regression adjusting for age, smoking, family history of CHD, vitamin C deficiency, blood pressure, plasma cholesterol concentration, and diabetes, the odds ratio (90% confidence interval) comparing heavy coffee drinkers with the low activity COMT genotype with those with the high activity or heterozygotic genotypes was 3.2 (1.2-8.4). Urinary adrenaline excretion increased with increasing coffee intake, being over two-fold in heavy drinkers compared with nondrinkers (p = 0.008 for trend). CONCLUSIONS/SIGNIFICANCE: Heavy coffee consumption increases the incidence of acute coronary events in men with low but not high COMT activity. Further studies are required to determine to which extent circulating catecholamines mediate the relationship between coffee intake and CHD.