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In studies following selective sampling protocols for secondary outcomes, conventional analyses regarding their appearance could provide misguided information. In the large type 1 diabetes prevention and prediction (DIPP) cohort study monitoring type 1 diabetes-associated autoantibodies, we propose to model their appearance via a multivariate frailty model, which incorporates a correlation component that is important for unbiased estimation of the baseline hazards under the selective sampling mechanism. As further advantages, the frailty model allows for systematic evaluation of the association and the differences in regression parameters among the autoantibodies. We demonstrate the properties of the model by a simulation study and the analysis of the autoantibodies and their association with background factors in the DIPP study, in which we found that high genetic risk is associated with the appearance of all the autoantibodies, whereas the association with sex and urban municipality was evident for IA-2A and IAA autoantibodies. publishedVersion

Background Increased left ventricular mass (LVM) predicts cardiovascular events and mortality. The objective of this study was to determine whether early-life exposures to body mass index (BMI) and systolic blood pressure (SPB) affects the left ventricular structure in adulthood. Methods We used longitudinal data from a 31-year follow-up to examine the associations between early-life (between ages 6-18) BMI and SPB on LVM in an adult population (N = 1864, aged 34-49). The burden of early-life BMI and SBP was defined as area under the curve. Results After accounting for contemporary adult determinants of LVM, early-life BMI burden associated significantly with LVM (3.61 g/SD increase in early-life BMI; [1.94 - 5.28], p 25 kg/m(2)) associated with 4.7% (2.5-6.9%, p 30kg/m(2)) resulted in a 21% (17.3-32.9%, p

BACKGROUND The European Randomized Study of Screening for Prostate Cancer has shown a 20% reduction in prostate cancer (PC) mortality by prostate-specific antigen-based screening. In addition, screening has been shown to reduce the risk of advanced PC. The objective of the current study was to analyze the impact of screening participation on the incidence of PC by risk group. METHODS The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance; they then remained in the once-screened group until the second screen and similarly for the possible third round. The control arm formed the reference group. Follow-up started at randomization and ended at the time of diagnosis of PC, emigration, or the end of 2015. PC cases were divided into risk groups according to European Association of Urology definitions. RESULTS The incidence of low-risk PC increased with the number of screens, whereas no clear relation with participation was noted in the intermediate-risk and high-risk cases. For patients with advanced PC, attending screening at least twice was associated with a lower risk. CONCLUSIONS Screening reduces the risk of advanced PC after only 2 screening cycles. A single screen demonstrated no benefit in terms of PC incidence. Repeated screening is necessary to achieve screening advantages.

Several prospective studies have shown an association between cows’ milk consumption and the risk of islet autoimmunity and/or type 1 diabetes. We wanted to study whether processing of milk plays a role. A population-based birth cohort of 6081 children with HLA-DQB1-conferred risk to type 1 diabetes was followed until the age of 15 years. We included 5545 children in the analyses. Food records were completed at the ages of 3 and 6 months and 1, 2, 3, 4 and 6 years, and diabetes-associated autoantibodies were measured at 3–12-month intervals. For milk products in the food composition database, we used conventional and processing-based classifications. We analysed the data using a joint model for longitudinal and time-to-event data. By the age of 6 years, islet autoimmunity developed in 246 children. Consumption of all cows’ milk products together (energy-adjusted hazard ratio 1·06; 95 % CI 1·02, 1·11; P = 0·003), non-fermented milk products (1·06; 95 % CI 1·01, 1·10; P = 0·011) and fermented milk products (1·35; 95 % CI 1·10, 1·67; P = 0·005) was associated with an increased risk of islet autoimmunity. The early milk consumption was not associated with the risk beyond 6 years. We observed no clear differences based on milk homogenisation and heat treatment. Our results are consistent with the previous studies, which indicate that high milk consumption may cause islet autoimmunity in children at increased genetic risk. The study did not identify any specific type of milk processing that would clearly stand out as a sole risk factor apart from other milk products.

Background and aims Carotid plaque is a specific sign of atherosclerosis and adults with carotid plaque are at increased risk for cardiovascular outcomes. Atherosclerosis has roots in childhood and pediatric guidelines provide cut-off values for cardiovascular risk factors. However, it is unknown whether these cut-offs predict adulthood advanced atherosclerosis. Methods The Cardiovascular Risk in Young Finns Study is a follow-up of children that begun in 1980 when 2653 participants with data for the present analyses were aged 3–18 years. In 2001 and 2007 follow-ups, in addition to adulthood cardiovascular risk factors, carotid ultrasound data was collected. Long-term burden, as the area under the curve, was evaluated for childhood (6–18 years) risk factors. To study the associations of guideline-based cut-offs with carotid plaque, both childhood and adult risk factors were classified according to clinical practice guidelines. Results Carotid plaque, defined as a focal structure of the arterial wall protruding into lumen >50% compared to adjacent intima-media thickness, was present in 88 (3.3%) participants. Relative risk for carotid plaque, when adjusted for age and sex, was 3.03 (95% CI, 1.76–5.21) for childhood dyslipidemia, 1.51 (95% CI, 0.99–2.32) for childhood elevated systolic blood pressure, and 1.93 (95% CI, 1.26–2.94) for childhood smoking. Childhood dyslipidemia and smoking remained independent predictors of carotid plaque in models additionally adjusted for adult risk factors and family history of coronary heart disease. Carotid plaque was present in less than 1% of adults with no childhood risk factors. Conclusions Findings reinforce childhood prevention efforts and demonstrate the utility of guideline-based cut-offs in identifying children at increased risk for adulthood atherosclerosis.

BackgroundAchieving a sustainable and healthy diet requires increased replacement of red meat with more sustainable foods. There is a call for novel methodologies to assess the potential of different interventions and policies in enhancing the transition from the current to more sustainable choices.ObjectiveWe aimed to characterize consumer clusters with similar preferences in protein sources, to compare the purchase prices of these foods, and to identify ongoing transitions from one protein source to another.DesignGrocery purchase data with individual attributes on 29,437 consenting loyalty card holders were analyzed over 2.3 year period. We designed a sequence analysis to group participants to clusters with similar purchase preferences over the follow-up period and to estimate transition probabilities between preferences. We studied the determinants of prevalent purchase profiles by ordinal logistic models.ResultsWe identified six participant profiles with similar preferences in four protein sources: red meat, poultry, fish, and plant-based foods. Red meat dominated the purchase preferences and showed the highest persistence over time. The majority (70%) of the participants demonstrated somewhat mixed purchase profiles. A step-by-step transition from red meat towards plant-based food preference seems most likely via poultry and fish. Overall, low income was not a barrier to a more sustainable purchase profile, while price may deter the purchase of fish. The most important resources in choosing more sustainable profiles were education and stage of family life.ConclusionsSocietal incentives for sustainable food choices seem most crucial at transition stages of life course and for the less educated. Here we also demonstrate that grocery purchase data offer a valuable tool for monitoring the progressive transition towards a healthy and sustainable food system.

Vegan diets are gaining popularity, also in families with young children. However, the effects of strict plant‐based diets on metabolism and micronutrient status of children are unknown. We recruited 40 Finnish children with a median age 3.5 years—vegans, vegetarians, or omnivores from same daycare centers—for a cross‐sectional study. They enjoyed nutritionist‐planned vegan or omnivore meals in daycare, and the full diets were analyzed with questionnaires and food records. Detailed analysis of serum metabolomics and biomarkers indicated vitamin A insufficiency and border‐line sufficient vitamin D in all vegan participants. Their serum total, HDL and LDL cholesterol, essential amino acid, and docosahexaenoic n‐3 fatty acid (DHA) levels were markedly low and primary bile acid biosynthesis, and phospholipid balance was distinct from omnivores. Possible combination of low vitamin A and DHA status raise concern for their visual health. Our evidence indicates that (i) vitamin A and D status of vegan children requires special attention; (ii) dietary recommendations for children cannot be extrapolated from adult vegan studies; and (iii) longitudinal studies on infant‐onset vegan diets are warranted., Nutritional and metabolic effects of strict vegan diets in young children are poorly understood. This first cross‐sectional study of preschool children reports that vegan diet remodels metabolome and lipidome and raises concern of their vitamin A and D statuses and essential amino acids.

Aims/hypothesis Diabetes and diabetes complications are a cause of substantial morbidity, resulting in early exits from the labour force and lost productivity. The aim of this study was to examine differences in early exits between people with type 1 and 2 diabetes and to assess the role of chronic diabetes complications on early exit. We also estimated the economic burden of lost productivity due to early exits. Methods People of working age (age 17–64) with diabetes in 1998–2011 in Finland were detected using national registers (Ntype 1 = 45,756, Ntype 2 = 299,931). For the open cohort, data on pensions and deaths, healthcare usage, medications and basic demographics were collected from the registers. The outcome of the study was early exit from the labour force defined as pension other than old age pension beginning before age 65, or death before age 65. We analysed the early exit outcome and its risk factors using the Kaplan–Meier method and extended Cox regression models. We fitted linear regression models to investigate the risk factors of lost working years and productivity costs among people with early exit. Results The difference in median age at early exit from the labour force between type 1 (54.0) and type 2 (58.3) diabetes groups was 4.3 years. The risk of early exit among people with type 1 diabetes increased faster after age 40 compared with people with type 2 diabetes. Each of the diabetes complications was associated with an increase in the hazard of early exit regardless of diabetes type compared with people without the complication, with eye-related complications as an exception. Diabetes complications partly but not completely explained the difference between diabetes types. The mean lost working years was 6.0 years greater in the type 1 diabetes group than in the type 2 diabetes group among people with early exit. Mean productivity costs of people with type 1 diabetes and early exit were found to be 1.4-fold greater compared with people with type 2 diabetes. The total productivity costs of incidences of early exits in the type 2 diabetes group were notably higher compared with the type 1 group during the time period (€14,400 million, €2800 million). Conclusions/interpretation We found a marked difference in the patterns of risk of early exit between people with type 1 and type 2 diabetes. The difference was largest close to statutory retirement age. On average, exits in the type 1 diabetes group occurred at an earlier age and resulted in higher mean lost working years and mean productivity costs. The potential of prevention, timely diagnosis and management of diabetes is substantial in terms of avoiding reductions in individual well-being and productivity. Graphical abstract

Background: Despite the elaborate history of statistical reporting in the USSR, Russia established modern population-based cancer registries (PBCR) only in the 1990s. The quality of PBCRs data has not been thoroughly analyzed. This study aims at assessing the comparability and validity of cancer statistics in regions of the Northwestern Federal District (NWFD) of Russia. Material and methods: Data from ten Russian regional PBCRs covering ∼13 million (∼5 million in St. Petersburg) were processed in line with IARC/IACR and ENCR recommendations. We extracted and analyzed all registered cases but focused on cases diagnosed between 2008 and 2017. For comparability and validity assessment, we applied established qualitative and quantitative methods. Results: Data collection in NWFD is in line with international standards. Distributions of diagnosis dates revealed higher variation in several regions, but overall, distributions are relatively uniform. The proportion of multiple primaries between 2008 and 2017 ranged from 6.7% in Vologda Oblast to 12.4% in Saint-Petersburg. We observed substantial regional heterogeneity for most indicators of validity. In 2013–2017, proportions of morphologically verified cases ranged between 61.7 and 89%. Death certificates only (DCO) cases proportion was in the range of 1–14% for all regions, except for Saint-Petersburg (up to 23%). The proportion of cases with a primary site unknown was between 1 and 3%. Certain cancer types (e.g., pancreas, liver, hematological malignancies, and CNS tumors) and cancers in older age groups showed lower validity. Conclusion: While the overall level of comparability and validity of PBCRs data of four out of ten regions of NWFD of Russia meets the international standards, differences between the regions are substantial. The local instructions for cancer registration need to be updated and implemented. The data validity assessment also reflects pitfalls in the quality of diagnosis of certain cancer types and patient groups. acceptedVersion

Background In January 2018, the legal limit for alcoholic beverages in grocery stores changed from 4.7 to 5.5 % alcohol. The increased availability of stronger beer, cider and ready-to-drink beverages was expected to increase the total amount of 100% alcohol bought. The study aimed to examine how the change in alcohol legislation affected the purchasing of 100% alcohol from grocery stores by comparing the years 2017 and 2018. Methods The study data consisted of 47,066 loyalty card holders of Finland's largest retail chain, who gave their consent and provided background information by an online questionnaire. The data contained the type, volume and alcoholic content of the purchases, from which we calculated the amount of 100% alcohol bought. The mean individual alcohol purchases in the years 2017 and 2018 were compared by age, gender, level of education and household income using repeated measurements ANOVA models. Results There was only a small, non-significant change in the total amount of 100% alcohol between 2017 and 2018 (mean 1.9 l and 2.0 l, respectively, p = 0.220). Lower income was associated with a decrease in total 100% alcohol purchased, whereas higher income groups showed an increase. Increase in 100% alcohol bought as ready-to-drink beverages was seen in all population groups. Conclusions The availability of stronger alcoholic beverages in grocery stores did not result in a notable overall increase in total purchases of 100% alcohol. The increased purchases of alcohol as ready-to-drink beverages were, on the average, compensated for by decreased purchases of alcohol as other beverages. The association of income with total alcohol purchases may indicate the effect of price in consumer behavior. Key messages The raise in the legal limit of alcohol content raised did not result in a significant increase in the total amount of 100% alcohol bought from grocery stores. Alcohol purchased as ready-to-drink beverages increased in all population groups.

Background Alcohol use epidemiology is facing challenges as survey response rates decline. In addition, population surveys fail to capture a large proportion of alcohol consumed and are expensive to conduct. This study aims to aid in complementing traditional epidemiological methods by validate grocery purchase data in the research on population alcohol use. Methods The LoCard study subjects were loyalty card holders of a grocery retail co-operative, which possessed more than 45 % market share in Finland. One third of those who consented to the analyses of their grocery purchases were presented a questionnaire including a Food Frequency Questionnaire on the web; N = 11,818 responded. The relationship between beer purchase frequency and self-reported beer drinking frequency was studied for association and agreement in different subgroups using crosstabulations and Poisson regression modeling. Results The association between beer purchase frequency and self-reported beer drinking frequency was good (Gamma = .556). The agreement between beer purchase frequency and drinking frequency was only fair (Kappa = .189). Limiting the data to those single adult households that reported making at least 61 % of their grocery purchases from this grocery retailer and collapsing the frequency categories to three instead of six increased the agreement to good (Kappa = .463). Conclusions Information on beer purchase frequency from the loyalty card database can be used to rank people according to their drinking frequency and to estimate beer drinking frequency with fair to good accuracy, depending on what share of grocery purchases they make from the grocery retailer in question.

Motivation Incorporating gene interaction data into the identification of ‘hit’ genes in genomic experiments is a well-established approach leveraging the ‘guilt by association’ assumption to obtain a network based hit list of functionally related genes. We aim to develop a method to allow for multivariate gene scores and multiple hit labels in order to extend the analysis of genomic screening data within such an approach. Results We propose a Markov random field-based method to achieve our aim and show that the particular advantages of our method compared with those currently used lead to new insights in previously analysed data as well as for our own motivating data. Our method additionally achieves the best performance in an independent simulation experiment. The real data applications we consider comprise of a survival analysis and differential expression experiment and a cell-based RNA interference functional screen. Availability and implementation We provide all of the data and code related to the results in the paper. Supplementary information Supplementary data are available at Bioinformatics online.

Background In adults, high blood pressure (BP), adverse serum lipids, and smoking associate with cognitive deficits. The effects of these risk factors from childhood on midlife cognitive performance are unknown. Objectives This study sought to investigate the associations between childhood/adolescence cardiovascular risk factors and midlife cognitive performance. Methods From 1980, a population-based cohort of 3,596 children (baseline age: 3 to 18 years) have been followed for 31 years in 3- to 9-year intervals. BP, serum lipids, body mass index, and smoking were assessed in all follow-ups. Cumulative exposure as the area under the curve for each risk factor was determined in childhood (6 to 12 years), adolescence (12 to 18 years), and young adulthood (18 to 24 years). In 2011, cognitive testing was performed in 2,026 participants aged 34 to 49 years. Results High systolic BP, elevated serum total-cholesterol, and smoking from childhood were independently associated with worse midlife cognitive performance, especially memory and learning. The number of early life risk factors, including high levels (extreme 75th percentile for cumulative risk exposure between ages 6 and 24 years) of systolic BP, total-cholesterol, and smoking associated inversely with midlife visual and episodic memory and visuospatial associative learning (–0.140 standard deviations per risk factor, p Conclusions Cumulative burden of cardiovascular risk factors from childhood/adolescence associate with worse midlife cognitive performance independent of adulthood exposure.

Background Alcohol consumption is a significant cause of disease, death and social harm, and it clusters with smoking tobacco and an unhealthy diet. Using automatically registered retail data for research purposes is a novel approach, which is not subject to underreporting bias. Based on loyalty card data (LoCard) obtained by a major Finnish retailer holding a market share of 47%, we examined alcohol expenditure and their associations with food and tobacco expenditures. Methods The data consisted of 1,527,217 shopping events in 2016 among 13,274 loyalty card holders from southern Finland. A K-means cluster analysis was applied to group the shopping baskets according to their content of alcoholic beverages. The differences in the absolute and relative means of food and tobacco between the clusters were tested by linear mixed models with the loyalty card holder as the random factor. Results By far, the most common basket type contained no alcoholic beverages, followed by baskets containing a small number of beers or ciders. The expenditure on food increased along with the expenditure on alcoholic beverages. The foods most consistently associated with alcohol purchases were sausages, soft drinks and snacks. The expenditure on cigarettes relative to total basket price peaked in the mid-price alcohol baskets. Conclusion Clustering of unhealthy choices occurred on the level of individual shopping events. People who bought many alcoholic beverages did not trim their food budget. Automatically registered purchase data provide valuable insight into the health behaviours of individuals and the population. Electronic supplementary material The online version of this article (10.1186/s12889-019-7096-3) contains supplementary material, which is available to authorized users.

Asthma has been reported to be associated with an increased risk of type 1 diabetes mellitus in childhood, but the reasons are unclear. We examined whether the use of antiasthmatic drugs was associated with the development of type 1 diabetes in childhood in a nationwide, register-based case-cohort study. We identified all children who were born January 1, 1995, through December 31, 2008, in Finland and diagnosed with type 1 diabetes by 2010 (n = 3,342). A 10% random sample from each birth-year cohort was selected as a reference cohort (n = 80,909). Information on all dispensed antiasthmatic drugs (Anatomical Therapeutic Chemical classification system code R03) during 1995–2009 was obtained, and associations between the use of antiasthmatic drugs and the development of type 1 diabetes were investigated using time-dependent and time-sequential Cox regression models. Dispensed inhaled corticosteroids and inhaled β-agonists were associated with an increased risk of type 1 diabetes after adjusting for other antiasthmatic drugs, asthma, sex, and birth decade (hazard ratio = 1.29, 95% confidence interval: 1.09, 1.52, and hazard ratio = 1.22, 95% confidence interval: 1.07, 1.41, respectively). These findings suggest that children using inhaled corticosteroids or inhaled β-agonists might be at increased risk of type 1 diabetes.

Several dietary factors have been suspected to play a role in the development of advanced islet autoimmunity (IA) and/or type 1 diabetes (T1D), but the evidence is fragmentary. A prospective population-based cohort of 6081 Finnish newborn infants with HLA-DQB1-conferred susceptibility to T1D was followed up to 15 years of age. Diabetes-associated autoantibodies and diet were assessed at 3- to 12-month intervals. We aimed to study the association between consumption of selected foods and the development of advanced IA longitudinally with Cox regression models (CRM), basic joint models (JM) and joint latent class mixed models (JLCMM). The associations of these foods to T1D risk were also studied to investigate consistency between alternative endpoints. The JM showed a marginal association between meat consumption and advanced IA: the hazard ratio adjusted for selected confounding factors was 1.06 (95% CI: 1.00, 1.12). The JLCMM identified two classes in the consumption trajectories of fish and a marginal protective association for high consumers compared to low consumers: the adjusted hazard ratio was 0.68 (0.44, 1.05). Similar findings were obtained for T1D risk with adjusted hazard ratios of 1.13 (1.02, 1.24) for meat and 0.45 (0.23, 0.86) for fish consumption. Estimates from the CRMs were closer to unity and CIs were narrower compared to the JMs. Findings indicate that intake of meat might be directly and fish inversely associated with the development of advanced IA and T1D, and that disease hazards in longitudinal nutritional epidemiology are more appropriately modeled by joint models than with naive approaches.

High content screening for drug discovery in cancer research relies increasingly on cell-based models, using microscopic imaging as a primary readout. In combination, microscopic imaging and cell culturing provide powerful tools for studying cancer-relevant cell biology in vitro. As a result, an enormous amount of complex biometric image data is generated that can be used for high throughput and high content analyses. We present a method for computationally efficient and flexible quantification of multicellular structures or tumor spheroids, conducted in a semi-unsupervised manner. Our phenotypic clustering approach is based on morphological features, in particular, on size and novel shape and texture features. It consists of multiple automated steps in which the information characterizing the most relevant morphological features is first extracted from the images, the dimension of the features is reduced, and finally, structures are clustered into biologically meaningful groups. Local central mom...

Purpose: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended. Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated. Results: Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60). Conclusions: Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.

Introduction The objective was to investigate trends in the incidence of recognised and suspected cases of occupational diseases in Finland 1975–2013, including variations by gender and industry. Methods The data consisted of recognised and suspected cases of occupational diseases registered in the Finnish Registry of Occupational Diseases (FROD) in 1975–2013. From the annual workforce statistics and data of FROD we calculated the incidence of occupational diseases and suspected occupational diseases per 10 000 employed. For time trends by industrial sector, we used a five-year moving average and Poisson’s regression analysis. Results Annual average rates of occupational diseases (per 10 000 employees) have varied from year to year. The total number was 25.0/10,000 in 1975 and 20.1/10,000 in 2013. Screening campaigns and legislative changes have caused temporary increases. The highest incidence rates in different industrial sectors were in mining and quarrying (9.87; 95% CI: 8.65 to 11.30), construction (9.11; 95% CI: 9.98 to 10.43), manufacturing (9.04; 95% CI: 7.93 to 10.36) and in agriculture (8.78; 95% CI: 7.69 to 10.06), when financial sector was the reference (1.0). During that time, women had significantly less occupational diseases than men (RR 0.62; 95% CI: 0.57 to 0.68). There is a more distinct decreasing trend from 2005 onwards: the average annual change in incidence was e.g. in agriculture −9.2%, in transportation −10.3% and in construction −4.7%. The average annual decline was greatest in upper limb strain injuries (−11.1%). Discussion This study provides a useful overview of the status of occupational diseases in Finland over several decades. These data are a valuable resource for investigating which occupations are at an increased risk and where the preventive actions should be focused on. It is important to study the long-term trends in the statistics of occupational diseases to discover the real trends behind year-to-year fluctuations.

Outlier detection covers the wide range of methods aiming at identifying observations that are considered unusual. Novelty detection, on the other hand, seeks observations among newly generated test data that are exceptional compared with previously observed training data. In many applications, the general existence of novelty is of more interest than identifying the individual novel observations. For instance, in high-throughput cancer treatment screening experiments, it is meaningful to test whether any new treatment effects are seen compared with existing compounds. Here, we present hypothesis tests for such global level novelty. The problem is approached through a set of very general assumptions, making it innovative in relation to the current literature. We introduce test statistics capable of detecting novelty. They operate on local neighborhoods and their null distribution is obtained by the permutation principle. We show that they are valid and able to find different types of novelty, e.g. location and scale alternatives. The performance of the methods is assessed with simulations and with applications to real data sets.

We examined maternal dietary intake of fatty acids and foods which are sources of fatty acids during lactation and whether they are associated with the risk of preclinical and clinical type 1 diabetes in the offspring.The subjects comprised a cohort of 2,939 mother-child pairs from the prospective Type 1 Diabetes Prediction and Prevention Study. Composition of maternal diet during the third month of lactation was assessed by a validated food frequency questionnaire. Among the children with HLA-conferred susceptibility to type 1 diabetes, 172 developed preclinical and 81 clinical diabetes. Average follow-up for preclinical type 1 diabetes was 7.5 years (range 0.2-14.0 years) and for clinical type 1 diabetes 7.7 years (0.2-14.0 years).Maternal intake of fatty acids during lactation was not associated with the risk of type 1 diabetes in the offspring. After adjusting for putative confounders, maternal total consumption of red meat and meat products during lactation was associated both with increased risk for preclinical [hazard ratio (HR) 1.19, 95 % CI 1.02-1.40, p = 0.038] and clinical type 1 diabetes (HR 1.27, 95 % CI 1.06-1.52, p = 0.025). In particular, consumption of processed meat products showed an association with increased risk for type 1 diabetes (HR 1.23, 95 % CI 1.02-1.48, p = 0.045). Maternal use of vegetable oils was associated with increased risk for preclinical type 1 diabetes (HR 1.21, 95 % CI 1.03-1.41, p = 0.023).Maternal consumption of red meat, especially processed meat, during lactation may increase the risk of type 1 diabetes.

Background The association between asthma and type 1 diabetes, two chronic, immune-mediated diseases, has been of longstanding interest, but the evidence is still conflicting. We examined this association in a large, nationwide case-cohort study among Finnish children, using a novel statistical approach. Methods Among the initial cohort of all children born between 1 January 1981 and 31 December 2008, those who were diagnosed with asthma (n = 81 473) or type 1 diabetes (n = 9541) up to age 16 years by the end of 2009 were identified from the Central Drug Register maintained by the Social Insurance Institution of Finland. A 10% random sample from each initial birth year cohort was selected as a reference cohort (n = 171 138). The association between asthma and type 1 diabetes was studied using a multistate modelling approach to estimate transition rates between healthy and disease states since birth. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to represent the change in the transition rate between the disease states. Results After adjusting for sex and birth decade, previous diagnosis of asthma increased the risk of subsequent type 1 diabetes by 41% (95% CI: 1.28, 1.54), whereas previous diagnosis of type 1 diabetes decreased the risk of subsequent asthma by 18% (95% CI: 0.69, 0.98). Conclusions The findings of the present study imply that the association between the diseases is more complex than previously thought, and its direction depends on the sequential appearance of the diseases.

Background: The European Randomised study of Screening for Prostate Cancer (ERSPC) is a multicentre, randomised screening trial on men aged 55-69 years at baseline without known prostate cancer (PrCa) at randomisation to an intervention arm invited to screening or to a control arm. The ERSPC has shown a significant 21% reduction in PrCa mortality at 13 years of follow-up. The effect of screening appears to vary across centres, for which several explanations are possible. We set to assess if the apparent differences in PrCa mortality reduction between the centres can be explained by differences in screening protocols. Methods: We examined the centre differences by developing a simulation model and estimated how alternative screening protocols would have affected PrCa mortality. Results: Our results showed outcomes similar to those observed, when the results by centres were reproduced by simulating the screening regimens with PSA threshold of 3 versus 4 ng/ml, or screening interval of two versus four years. The findings suggest that the differences are only marginally attributable to the different screening protocols. Conclusion: The small screening impact in Finland was not explained by the differences in the screening protocols. A possible reason for it was the contamination of and the unexpectedly low PrCa mortality in the Finnish control arm. (C) 2016 Elsevier Ltd. All rights reserved.

Background Employment protects and fosters health. Occupational health services, particularly in Finland, have a central role in protecting employee health and preventing work ability problems. However, primary care within occupational health services is currently underused in informing preventive activities. This study was designed to assess whether the recording of work ability problems and improvement of follow-up of work-related primary care visits can reduce sickness absences and work disability pensions after 1 year. Methods/design A pragmatic trial will be conducted using patient electronic registers and registers of the central pensions agency in Finland. Twenty-two occupational health centres will be randomised to intervention and control groups. Intervention units will receive training to improve recording of work ability illnesses in the primary care setting and improved follow-up procedures. The intervention impact will be assessed through examining rates of sickness absence across intervention and control clinics as well as before and after the intervention. Discussion The trial will develop knowledge of the intervention potential of primary care for preventing work disability pensions and sickness absence. The use of routine patient registers and pensions registers to assess the outcomes of a randomised controlled trial will bring forward trial methodology, particularly when using register-based data. If successful, the intervention will improve the quality of occupational health care primary care and contribute to reducing work disability. Trial registration ISRCTN Registry reference number ISRCTN45728263. Registered on 18 April 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2076-3) contains supplementary material, which is available to authorized users.

Breastfeeding, age at introduction of foods, and food diversity in infancy were studied for associations with advanced islet autoimmunity and type 1 diabetes. During 1996--2004, a total of 5,915 newborns with human leukocyte antigen-conferred susceptibility to type 1 diabetes were enrolled in the prospective Finnish Type 1 Diabetes Prediction and Prevention Nutrition Study. Children were assessed at intervals of 3-12 months for the appearance of 4 types of islet autoantibodies and type 1 diabetes up to the age of 15 years. Survival models indicated the 3 variables of interest were not associated with advanced islet autoimmunity or type 1 diabetes in the cohort. Early introduction of solid foods was associated with increased risk of advanced islet autoimmunity in children up to age 3 years (for3 months vs.4 months, hazard ratio = 2.33, 95% confidence interval: 1.39, 3.91; for 3-4 months vs.4 months, hazard ratio = 2.18; 95% confidence interval: 1.38, 3.47) but not in longer follow-up (P for interaction = 0.046). Similar results were observed for age at introduction of roots, cereals, egg, and meat relative to risk of advanced islet autoimmunity. No consistent, long-term associations between infant feeding and advanced islet autoimmunity or type 1 diabetes were observed.

Background: Evidence for the role of food consumption during childhood in the development of beta cell autoimmunity is scarce and fragmentary. Objective: We set out to study the associations of longitudinal food consumption in children with the development of advanced beta cell autoimmunity. Design: Children with advanced beta cell autoimmunity (n = 232) (ie, with repeated positivity for antibodies against islet cells) together with positivity for at least one of the other 3 antibodies analyzed or clinical type 1 diabetes were identified from a prospective birth cohort of 6069 infants with HLA-DQB1-conferred susceptibility to type I diabetes who were born in 1996-2004, with the longest follow-up to the age of 11 y. Repeated 3-d food records were completed by the families and daycare personnel. Diabetes-associated autoantibodies and diets were measured at 3-12-mo intervals. Four control subjects, who were matched for birth date, sex, area, and genetic risk, were randomly selected for each case. Results: in the main food groups, only intakes of cow-milk products (OR: 1.05; 95% CI: 1.00, 1.10) and fruit and berry juices (OR: 1.09; 95% CI: 1.02, 1.12) were significantly, although marginally, associated with advanced beta cell autoimmunity. The consumption of fresh milk products and cow milk-based infant formulas was related to the endpoint, whereas no evidence was shown for consumption of sour milk products and cheese. The intake of fat from all milk products and protein from fresh milk products was associated with risk of advanced beta cell autoimmunity. Conclusion: Intakes of cow milk and fruit and berry juices could be related to the development of advanced beta cell autoimmunity. This trial was registered at clinicaltrials.gov as number NCT00223613. Am J Clin Nutr 2012;95:471-8.

Fatty acid concentrations in blood are potential biomarkers of dietary fat intake, but methodological studies among children are scarce. The large number of fatty acids and their complex interrelationships pose a special challenge in research on fatty acids. Our target was to assess the interrelationships between the total fatty acid profiles in diet and serum of young children. The study subjects were healthy control children from the birth cohort of the Type 1 Diabetes Prediction and Prevention Study. A 3-day food record and a frozen serum sample were available from 135 children at the age of 1 year, from 133 at 2 years, and from 92 at 3 years. The relationship between dietary and serum fatty acid profiles was analysed using canonical correlation analysis. The consumption of fatty milk correlated positively with serum fatty acids, pentadecanoic acid, palmitic acid and conjugated linoleic acid (CLA) at all ages. Correlations between dietary and serum eicosapentaenoic and/or docosahexaenoic acid were observed at 2 and 3 years of age. Serum linoleic acid was positively associated with the consumption of infant formula at the age of 1 year, and with the consumption of vegetable margarine at 2 and 3 years. The results indicate a high quality of the 3-day food records kept by parents and other caretakers of the children, and suitability of non-fasting, un-fractioned serum samples for total fatty acid analyses. The correlation between intake of milk fat and serum proportion of CLA is a novel finding.

Diabet. Med. 28, 965–971 (2011) Abstract Aims Early introduction of supplementary foods has been implicated to play a role in the development of s-cell autoimmunity. We set out to study the effects of breastfeeding and age at introduction of supplementary foods on the development of s-cell autoimmunity. Methods A prospective birth cohort of 6069 infants with HLA-DQB-conferred susceptibility to Type 1 diabetes was recruited between 1996 and 2004. Antibodies against islet cells, insulin, glutamate dehydroxylase and islet antigen 2 were measured at 3- to 12-month intervals. The families recorded at home the age at introduction of new foods and, for each visit, completed a structured dietary questionnaire. The endpoint was repeated positivity for islet cell antibodies plus at least one other antibody and/or clinical Type 1 diabetes (n = 265). Results Early introduction of root vegetables (by the age of 4 months) was related to increased risk of developing positivity for the endpoint [hazard ratio (95% CI) for the earliest third 1.75 (1.11–2.75) and for the middle third 1.79 (1.22–2.62) compared with the last third (> 4 months), likelihood ratio test P = 0.006], independently of the introduction of other foods and of several putative socio-demographic and perinatal confounding factors. Introducing wheat, rye, oats and/or barley cereals (P = 0.013) and egg (P = 0.031) early was related to an increased risk of the endpoint, but only during the first 3 years of life. Conclusions Early introduction of root vegetables during infancy is independently associated with increased risk of s-cell autoimmunity among Finnish children with increased genetic susceptibility to Type 1 diabetes.

The duration of the period of time during which diet should be recorded for sufficiently accurate results on the usual intake of an individual is an especially challenging issue in prospective studies among children. We set out to describe nutrient intake variability in preschoolers and to determine the number of record days required (D) to estimate intake of energy and thirty-two nutrients. The diet and the use of dietary supplements were assessed with three consecutive daily food records including one weekend day in 1639 children participating in the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project (DIPP) in Finland. Variance ratios and D stratified by sex and age groups were calculated for 455 (1-year-old), 471 (3-year-old) and 713 (6-year-old) children (born between 1998 and 2003). Within:between variance ratios and D increase with increasing age, and are slightly higher for girls. Vitamin A, cholesterol, n-3 and n-6 fatty acids, β-carotene and folate intakes require the most replicates. Including supplemental intake has an impact on the variance estimates according to the proportion of supplement users. In the DIPP Nutrition Study with 3 d food records, the correlation coefficients between observed and true intakes of energy and thirty-two nutrients averaged 0·91 in 1-year-old children, 0·79 in 3-year-old children and 0·74 in 6-year-old children. For providing accurate nutrient intake estimates, three replicates of food records are reasonable in 1-year-old children but must be questioned for several nutrients in 3- and 6-year-old children. The accuracy of ranking boys is greater than that for girls.

Aim Reactive oxygen intermediates have been implicated in mediating the destruction of insulin-producing beta cells and antioxidant nutrients thought to protect against such a process. This study aimed to assess the associations between serum α- and β-carotene concentrations, and the risk of advanced beta-cell autoimmunity, in children with HLA-conferred susceptibility to type 1 diabetes. Methods This case-control study, comprising 108 case children with advanced beta-cell autoimmunity and 216 matched control children, was nested within the nutrition study of the Type 1 Diabetes Prediction and Prevention (DIPP) birth cohort. Serum α- and β-carotene samples were collected each year from the age of 1 to 6years. For each case-control group, serum samples were analyzed up to the time of seroconversion in the case children. Associations were studied using a conditional logistic-regression model. Results Neither serum α- nor β-carotene concentration was significantly associated with the risk of advanced beta-cell autoimmunity. There was marginal evidence ( P =0.049) of an inverse association between serum β-carotene concentration and the risk of developing advanced beta-cell autoimmunity at a time closest to seroconversion after adjusting for parental education, maternal age, duration of gestation, diabetes in first-degree relatives, number of earlier deliveries and maternal smoking during pregnancy. Conclusion The present study data provided no clear evidence to support an association between serum α- or β-carotene concentration and advanced beta-cell autoimmunity.

Objective To study the characteristics of large-scale loyalty card data obtained in Finland, and to evaluate their potential and challenges in health research. Methods We contacted the holders of a certain loyalty card living in a specific region in Finland via email, and requested their electronic informed consent to obtain their basic background characteristics and grocery expenditure data from 2016 for health research purposes. Non-participation and the characteristics and expenditure of the participants were mainly analysed using summary statistics and figures. Results The data on expenditure came from 14,595 (5.6% of those contacted) consenting loyalty card holders. A total of 68.5% of the participants were women, with an average age of 46 years. Women and residents of Helsinki were more likely to participate. Both young and old participants were underrepresented in the sample. We observed that annual expenditure represented roughly two-thirds of the nationally estimated annual averages. Customers and personnel differed in their characteristics and expenditure, but not so much in their most frequently bought items. Conclusions Loyalty card data from a major retailer enabled us to reach a large, heterogeneous sample with fewer resources than conventional surveys of the same magnitude. The potential of the data was great because of their size, coverage, objectivity, and long periods of dynamic data collection, which enables timely investigations. The challenges included bias due to non-participation, purchases in other stores, the level of detail in product grouping, and the knowledge gaps in what is being consumed and by whom. Loyalty card data are an underutilised resource in research, and could be used not only in retailers’ activities, but also for societal benefit.

The diet of pre-school children is determined by the parents and carers. The aim of the present study was to describe dietary clusters of pre-school children and their mothers in Finland, and analyse the similarity of dietary clusters within child–mother pairs. The present study comprised the mothers (n 4862) whose child was recruited in the Type 1 Diabetes Prediction and Prevention Nutrition Study and the children belonging to selected, cross-sectional age groups of 1 year (n 719), 3 years (n 708) and 6 years (n 841). The dietary data were collected from children by 3-d food records and from mothers by a FFQ validated for pregnant women. The food consumption data were analysed for patterns by hierarchical cluster analysis. Three main dietary clusters were identified in children: ‘healthy’ and ‘traditional’ in all three age groups, and ‘ready-to-eat baby foods’ in 1-year-olds and ‘fast foods, sweet’ in the older children. Six main clusters were identified among the mothers who completed a FFQ for their diet during pregnancy. Some familial dependence between dietary clusters of mother–child pairs was observed in 6-year-old children but not in younger children. Younger age and lower educational level of the mother were associated with the cluster ‘fast food, sweet’ only at the age of 3 years. The diets of pre-school children vary by age and only a slight similarity within dietary clusters of mother–child pairs was observed.

BACKGROUND: Type 1 diabetes may have its origins in the fetal period of life. Free radicals were implicated in the cause of type 1 diabetes. It was hypothesized that antioxidant nutrients could protect against type 1 diabetes. OBJECTIVE: We assessed whether high maternal intake of selected dietary antioxidants during pregnancy is associated with a reduced risk of advanced beta cell autoimmunity in the child, defined as repeated positivity for islet cell antibodies plus >/=1 other antibody, overt type 1 diabetes, or both. DESIGN: The study was carried out as part of the population-based birth cohort of the Type 1 Diabetes Prediction and Prevention Project. The data comprised 4297 children with increased genetic susceptibility to type 1 diabetes, born at the University Hospital of Oulu or Tampere, Finland, between October 1997 and December 2002. The children were monitored for diabetes-associated autoantibodies from samples obtained at 3-12-mo intervals. Maternal antioxidant intake during pregnancy was assessed postnatally with a self-administered food-frequency questionnaire, which contained a question about consumption of dietary supplements. RESULTS: Maternal intake of none of the studied antioxidant nutrients showed association with the risk of advanced beta cell autoimmunity in the child. The hazard ratios, indicating the change in risk per a 2-fold increase in the intake of each antioxidant, were nonsignificant and close to 1. CONCLUSION: High maternal intake of retinol, beta-carotene, vitamin C, vitamin E, selenium, zinc, or manganese does not protect the child from development of advanced beta cell autoimmunity in early childhood.

The aim of our study was to assess the associations of serum alpha- and gamma-tocopherol concentrations with the risk of advanced beta cell autoimmunity in children with HLA-conferred genetic susceptibility to type 1 diabetes mellitus.A case-control study with 108 cases with advanced beta cell autoimmunity and 216 matched control participants nested within the birth cohort of the Type 1 Diabetes Prediction and Prevention Project. A serum sample for vitamin E analyses was collected from all the children in the cohort at the age of 1 year and thereafter at 12 month intervals. For each case-control group, all the repeated serum samples up to the age of seroconversion to autoantibody positivity in the case were analysed. A conditional logistic regression model was used to determine potential associations between seroconversion and serum tocopherol concentrations.Serum alpha- or gamma-tocopherol concentrations were not significantly associated with the risk of advanced beta cell autoimmunity. The odds ratio (95% CI) for micromol/l increase in serum concentration of the first-year sample was 0.97 (0.92-1.03) for alpha-tocopherol and 1.10 (0.70-1.74) for gamma-tocopherol. However, there was an interaction between high values of gamma-tocopherol at the age of 1 year and the time of seroconversion (p = 0.024).It seems unlikely that high concentrations of alpha- or gamma-tocopherol protect against advanced beta cell autoimmunity in young children.

Background— The American Heart Association has defined a new metric of ideal cardiovascular health as part of its 2020 Impact Goals. We examined whether psychosocial factors in youth predict ideal cardiovascular health in adulthood. Methods and Results— Participants were 477 men and 612 women from the nationwide Cardiovascular Risk in Young Finns Study. Psychosocial factors were measured from cohorts 3 to 18 years of age at the baseline of the study, and ideal cardiovascular health was examined 27 years later in adulthood. The summary measure of psychosocial factors in youth comprised socioeconomic factors, emotional factors, parental health behaviors, stressful events, self-regulation of the child, and social adjustment of the child. There was a positive association between a higher number of favorable psychosocial factors in youth and greater ideal cardiovascular health index in adulthood (β=0.16; P P P P =0.004) were the strongest predictors of ideal cardiovascular health in adulthood. Conclusions— The findings suggest a dose-response association between favorable psychosocial factors in youth and cardiovascular health in adulthood, as defined by the American Heart Association metrics. The effect seems to persist throughout the range of cardiovascular health, potentially shifting the population distribution of cardiovascular health rather than simply having effects in a high-risk population.

Organotypic, three dimensional (3D) cell culture models of epithelial tumour types such as prostate cancer recapitulate key aspects of the architecture and histology of solid cancers. Morphometric analysis of multicellular 3D organoids is particularly important when additional components such as the extracellular matrix and tumour microenvironment are included in the model. The complexity of such models has so far limited their successful implementation. There is a great need for automatic, accurate and robust image segmentation tools to facilitate the analysis of such biologically relevant 3D cell culture models. We present a segmentation method based on Markov random fields (MRFs) and illustrate our method using 3D stack image data from an organotypic 3D model of prostate cancer cells co-cultured with cancer-associated fibroblasts (CAFs). The 3D segmentation output suggests that these cell types are in physical contact with each other within the model, which has important implications for tumour biology. Segmentation performance is quantified using ground truth labels and we show how each step of our method increases segmentation accuracy. We provide the ground truth labels along with the image data and code. Using independent image data we show that our segmentation method is also more generally applicable to other types of cellular microscopy and not only limited to fluorescence microscopy. Public Library of Science open access

The efficacy and safety of a single intravenous (I.V.) infusion of clodronate 1500 mg or 900 mg was compared with a single I.V. infusion of pamidronate 90 mg in the treatment of malignant hypercalcemia. Primary efficacy data from two separate, but parallel, randomized double-blind controlled multi-center studies (N = 63), involving patients with malignant hypercalcemia (S-Ca(cor)2.68 mmol/l), were pooled along with results from a study (N = 4), in which an open I.V. phase was followed by a randomized oral phase. The primary efficacy variable, the proportion of normocalcemic patients at day 5 could be evaluated from 51 subjects. Of them, 21 were in the clodronate 1500 mg group, 10 in the clodronate 900 mg group and 20 in the pamidronate 90 mg group. After the rehydration, the patients were given a single I.V. infusion of clodronate 1500 mg, clodronate 900 mg or pamidronate 90 mg. The patients were followed up for five days and S-Ca(cor) was measured daily. At day 5, a total of 16 patients (76%) in the clodronate 1500 mg group, six patients (60%) in the clodronate 900 mg group and 17 patients (85%) in the pamidronate 90 mg group were normocalcemic, the differences between the treatment groups being statistically non-significant. The differences in the mean S-Ca(cor) between the treatment groups were statistically non-significant. I.V. clodronate given either as 900 mg or 1500 mg single-dose was safe and well tolerated.

Introduction: Long-term safety and tolerance is paramount when treating women who are otherwise healthy after the primary adjuvant therapy of breast cancer. Efficacy and limited safety results of a large-scale clinical trial, using adjuvant oral clodronate to prevent bone metastases in primary breast cancer patients, have been reported previously, demonstrating a reduction in the rate of bone metastases during treatment. Here we present expanded safety and tolerability results for clodronate treatment from this trial (cut-off date extended from June 1997 to June 2000). Study Design and Methods: For this randomised, double-blind, placebocontrolled, multicentre study, patients were enrolled and randomised to receive oral clodronate (Bonefos®) 1600 mg/day or placebo for 2 years. The total median treatment period plus follow-up was 5.5 years. Adverse events (AEs) and laboratory parameters were followed up regularly for the total study period. The 9 5% CIs were estimated for the difference in the rate of AEs between the treatment groups. Patients: A total of 1079 women with primary operable breast cancer were enrolled to the study; 538 received clodronate and 541 received placebo. Results: Overall incidence of AEs (96.5% of the patients) was the same in both treatment groups, although gastrointestinal disorders were significantly more frequent in the clodronate group during the total study period (66% vs 56.2%; 95% CI 4.0-15.6; p < 0.05). This was mainly due to an increase in non-severe diarrhoea beginning 3–4 months after treatment start. Serious AEs (SAEs) were reported for 39.4% of the patients receiving clodronate and 44.5% of those receiving placebo; no drug-related (clodronate or placebo) SAEs were identified. Clodronate significantly lowered mortality (98 deaths vs 129 deaths; hazard ratio 0.77; 95% CI 0.59–1.00; p = 0.047) reducing the risk of death over the total study period by 23%. AEs caused 58 early discontinuations (five drug-related events) in the clodronate group and 43 discontinuations (three drug-related events) in the placebo group. Conclusion: These results indicate that in women with early breast cancer receiving adjuvant systemic therapy, oral clodronate for 2 years is generally well tolerated with no serious long-term sequelae, providing a safe, long-term therapy in the adjuvant setting.

Objective Affordability is known to be a key determinant of alcohol consumption, possibly even more important in adolescence. Relating adolescent drinking pattern developments over a period of time to trends in adolescent income can yield information on the significance of parental control of adolescent income. Design Biannual repeated cross-sectional surveys. Setting Nationally representative samples. Participants 14-year-old adolescents in the period 1983–2013 in Finland (N=33 771). Results Adolescents9 alcohol drinking pattern was significantly associated with their disposable income. The OR for monthly drunkenness versus abstinence was 6.6 (95% CI 5.0 to 8.8) among girls and 9.0 (6.3 to 13.0) among boys in the highest income group compared with the lowest. However, the association between income and drinking pattern weakened considerably during the 30-year period. Conclusions Disposable income has been a significant predictor of adolescent alcohol drinking in the past 30 years. However, in the recent years, the amount of disposable money has decreased in importance.

The aim of the present study was to examine the associations between the maternal intake of fatty acids during pregnancy and the risk of preclinical and clinical type 1 diabetes in the offspring. The study included 4887 children with human leucocyte antigen (HLA)-conferred type 1 diabetes susceptibility born during the years 1997–2004 from the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal diet was assessed with a validated FFQ. The offspring were observed at 3- to 12-month intervals for the appearance of type 1 diabetes-associated autoantibodies and development of clinical type 1 diabetes (average follow-up period: 4·6 years (range 0·5–11·5 years)). Altogether, 240 children developed preclinical type 1 diabetes and 112 children developed clinical type 1 diabetes. Piecewise linear log-hazard survival model and Cox proportional-hazards regression were used for statistical analyses. The maternal intake of palmitic acid (hazard ratio (HR) 0·82, 95 % CI 0·67, 0·99) and high consumption of cheese during pregnancy (highest quarter v. intermediate half HR 0·52, 95 % CI 0·31, 0·87) were associated with a decreased risk of clinical type 1 diabetes. The consumption of sour milk products (HR 1·14, 95 % CI 1·02, 1·28), intake of protein from sour milk (HR 1·15, 95 % CI 1·02, 1·29) and intake of fat from fresh milk (HR 1·43, 95 % CI 1·04, 1·96) were associated with an increased risk of preclinical type 1 diabetes, and the intake of low-fat margarines (HR 0·67, 95 % CI 0·49, 0·92) was associated with a decreased risk. No conclusive associations between maternal fatty acid intake or food consumption during pregnancy and the development of type 1 diabetes in the offspring were detected.

The complex network of diet, lifestyle and socio-demographic exposures are hampering the identification of groups that are more likely than others to become obese. Traditional regression models are often limited in exploring the mutual importance of exposures: we cannot make very good inferences about what variables are actually important and why. Machine learning techniques may provide a solution to investigate the network between exposures and eventually develop decision rules for obesity risk estimation in clinical work. The population-based cross-sectional study …

AIMS: To test if changes in national alcohol policy have had an impact on alcohol use among 12- to 18-year-old adolescents in Finland over a 30-year period. METHODS: Frequencies of drinking any amounts of alcohol and drinking alcohol until really drunk from bi-annual repeated cross-sectional surveys from 1981 to 2011 were examined against a national alcohol policy review using nationally representative samples of 12-, 14-, 16- and 18-year-old adolescents (n = 99,724) in Finland. RESULTS: Twelve-year-olds' alcohol drinking remained rare throughout the period. Drinking among 18-year-olds generally increased throughout the period. Significant increases until the late 1990s and decreases thereafter were observed in 14- and 16-year-olds' drinking patterns. A sharp increase was predicted between 2003 and 2005 as a result of EU-related processes, but instead decrease was observed among 14-16-year-olds. The tests of hypothesized decrease from 2005 to 2011 due to tightening alcohol policy including several tax raises produced mixed results. CONCLUSION: Alcohol policy changes between 1981 and 2011 seem not to have had noticeable influence on alcohol drinking or drunkenness among the under-aged in Finland. Conspicuous increases seen in population total consumption in association with EU-related developments have not materialized among adolescents. Language: en

N-3 (omega-3) fatty acids have been reported to decrease the risk for development of beta-cell autoimmunity and clinical type I diabetes. We set out to examine whether different serum fatty acids are associated with the development of advanced beta-cell autoimmunity in children carrying human leukocyte antigen DQ beta-1 (HLA-DQB1)-conferred susceptibility to type I diabetes.Within a cohort, serum total fatty acid composition of 108 children with advanced beta-cell autoimmunity and of 216 matched persistently autoantibody-negative controls was analyzed using gas chromatography. Non-fasting serum samples were obtained annually at the ages of 1-6 years. Conditional logistic regression was applied to analyze the associations between advanced beta-cell autoimmunity and serum fatty acids.The serum fatty acid profile of myristic acid (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.09-2.00, P=0.011), pentadecanoic acid (OR 1.65, 95% CI 1.19-2.28, P=0.003), palmitoleic acid isomers 16:1 n-7 (omega-7) (OR 1.41, 95% CI 1.03-1.92, P=0.030) and 16:1 n-9 (omega-9) (OR 1.45, 95% CI 1.05-2.01, P=0.026) and conjugated linoleic acid (OR 1.67, 95% CI 1.16-2.41, P=0.006) closest to the time of the appearance of multiple autoantibodies were positively associated with the risk of advanced beta-cell autoimmunity after adjustment for potential confounding factors. Serum linoleic acid showed inverse, marginal association with the end point.Serum biomarkers of milk and ruminant meat fat consumption are directly associated and linoleic acid is inversely associated with advanced beta-cell autoimmunity in children with HLA-conferred susceptibility to type I diabetes.

Summary Background Vitamin D is known to have a number of immunological effects and it may play a role in preventing allergic diseases. Objectives To study the effect of maternal intake of vitamin D during pregnancy on the emergence of asthma, allergic rhinitis (AR), and atopic eczema by the age of 5 years in children with HLA-DQB1-conferred susceptibility for type 1 diabetes. Methods Children (1669) participating in the population-based birth cohort study were followed for asthma, AR, and atopic eczema assessed by validated questionnaire at 5 years. Maternal diet was assessed by a food-frequency questionnaire. Results The mean maternal intake of vitamin D was 5.1 (SD 2.6) μg from food and 1.4 (2.6) μg from supplements. Only 32% of the women were taking vitamin D supplements. When adjusted for potential confounders, maternal intake of vitamin D from food was negatively related to risk of asthma [hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.64–0.99] and AR [HR 0.85; 95% CI 0.75–0.97]. Vitamin D supplements alone were not associated with any outcome. Adjustment for maternal intake of other dietary factors did not change the results. Conclusion Maternal vitamin D intake from foods during pregnancy may be negatively associated with risk of asthma and AR in childhood.

Aims: To assess the relationship between negative experiences and frequency of alcohol drinking and drunkenness among 15- to 16-year-old adolescents in Finland. Methods: A school-based survey as part of the European School Project on Alcohol and Other Drugs (ESPAD) conducted in Finland in 2003. Nationally representative sample of Finnish adolescents, aged 15–16 (n = 3,321). Response rate 92%. Negative experiences, alcohol use and drunkenness were assessed using a self-administered questionnaire. Logistic regression analysis was used to examine the relationship between negative experiences and drinking experience. Results: Prevalence of negative experiences increased with increased frequency of drinking and drunkenness. Certain harms (troubles with the police, engaging in regretted and unprotected sexual intercourse) were experienced primarily with frequent drinking and drunkenness (>20 occasions). Logistic regression analysis indicated that only the drunkenness-related drinking style was significantly related to troubles with the police and engaging in sexual intercourse regretted the next day. Conclusions: While under-aged youths experience many problems in relationship to their alcohol use, certain problems are highly associated with frequent and heavy drinking, especially with drunkenness-related drinking style. These findings should be acknowledged when implementing effective alcohol education and alcohol-related policies to reduce under-aged alcohol use and related harms.

Recently, new nonparametric multivariate extensions of the univariate sign methods have been proposed. Randles (2000) introduced an affine invariant multivariate sign test for the multivariate location problem. Later on, Hettmansperger and Randles (2002) considered an affine equivariant multivariate median corresponding to this test. The new methods have promising efficiency and robustness properties. In this paper, we review these developments and compare them with the classical multivariate analysis of variance model. A new SAS/IML tool for performing a spatial sign based multivariate analysis of variance is introduced.

PURPOSE: The development of bone metastases depends on tumor-induced osteoclastic resorption of bone, which may be inhibited by the antiosteolytic bisphosphonate clodronate. Given to patients with primary breast cancer, clodronate might reduce the subsequent incidence of bone metastases. PATIENTS AND METHODS: This double-blind, multicenter trial accrued 1,069 assessable patients with operable breast cancer between 1989 and 1995. All patients received surgery, radiotherapy, chemotherapy, and tamoxifen as required. Patients were randomized to receive oral clodronate 1,600 mg/d or a placebo for 2 years starting within 6 months of primary treatment. The primary end point was relapse in bone, analyzed on an intent-to-treat basis, during the medication period and during the total follow-up period (median follow-up, 2,007 days). Secondary end points were relapse in other sites, mortality, and toxicity. RESULTS: During the total follow-up period, there was a nonsignificant reduction in occurrence of bone metastases (clodronate, n = 63; placebo, n = 80; hazards ratio [HR], 0.77; 95% confidence interval [CI], 0.56 to 1.08; P = .127). During the medication period there was a significant reduction in the occurrence of bone metastases (clodronate, n = 12; placebo, n = 28; HR, 0.44; 95% CI, 0.22 to 0.86; P = .016). The occurrence of nonosseous metastases was similar (clodronate, n = 112; placebo, n = 128; P = .257), but there was a significant reduction in mortality (clodronate, n = 98; placebo, n = 129; P = .047) during the total follow-up period. CONCLUSION: Clodronate, given to patients with primary operable breast cancer, may reduce the occurrence of bone metastases, although this reduction was only significant during this medication period. There was a significant reduction in mortality.

Two recent US cohort studies suggest that current levels of particulate pollution in urban air are associated not only with short-term, but also with long-term increases in cardiorespiratory morbidity and mortality. The aim of the present analyses was to evaluate the change in life expectancy assuming the long-term increase in mortality rates as suggested by these studies. The method of competing causes of death was used and the effect of particulate air pollution on life expectancy was found to be notable in countries with high cardiovascular mortality like the US.