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  • Koskinen, Lotta L E; Seppälä, Eija H; Belanger, Janelle M; Arumilli, Meharji; Hakosalo, Osmo; Jokinen, Päivi; Nevalainen, Elisa M; Viitmaa, Ranno; Jokinen, Tarja S; Oberbauer, Anita M; Lohi, Hannes (BioMed Central, 2015)
    Abstract Background Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (pc = 2.9e–07, pGWAS = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (praw = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.
  • Koskinen, Lotta L E; Seppälä, Eija H; Belanger, Janelle M; Arumilli, Meharji; Hakosalo, Osmo; Jokinen, Päivi; Nevalainen, Elisa M; Viitmaa, Ranno; Jokinen, Tarja S; Oberbauer, Anita M; Lohi, Hannes (BioMed Central, 2015)
    Abstract Background Idiopathic epilepsy is a common neurological disease in human and domestic dogs but relatively few risk genes have been identified to date. The seizure characteristics, including focal and generalised seizures, are similar between the two species, with gene discovery facilitated by the reduced genetic heterogeneity of purebred dogs. We have recently identified a risk locus for idiopathic epilepsy in the Belgian Shepherd breed on a 4.4 megabase region on CFA37. Results We have expanded a previous study replicating the association with a combined analysis of 157 cases and 179 controls in three additional breeds: Schipperke, Finnish Spitz and Beagle (pc = 2.9e–07, pGWAS = 1.74E-02). A targeted resequencing of the 4.4 megabase region in twelve Belgian Shepherd cases and twelve controls with opposite haplotypes identified 37 case-specific variants within the ADAM23 gene. Twenty-seven variants were validated in 285 cases and 355 controls from four breeds, resulting in a strong replication of the ADAM23 locus (praw = 2.76e–15) and the identification of a common 28 kb-risk haplotype in all four breeds. Risk haplotype was present in frequencies of 0.49–0.7 in the breeds, suggesting that ADAM23 is a low penetrance risk gene for canine epilepsy. Conclusions These results implicate ADAM23 in common canine idiopathic epilepsy, although the causative variant remains yet to be identified. ADAM23 plays a role in synaptic transmission and interacts with known epilepsy genes, LGI1 and LGI2, and should be considered as a candidate gene for human epilepsies.
  • Liu, Chengyu; Louhimo, Riku; Laakso, Marko; Lehtonen, Rainer; Hautaniemi, Sampsa (BioMed Central, 2015)
    Abstract Background Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. Methods We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. Results We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. Conclusions We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at http://csbi.ltdk.helsinki.fi/pub/czliu/DERA/ .
  • Liu, Chengyu; Louhimo, Riku; Laakso, Marko; Lehtonen, Rainer; Hautaniemi, Sampsa (BioMed Central, 2015)
    Abstract Background Histologically similar tumors even from the same anatomical position may still show high variability at molecular level hindering analysis of genome-wide data. Leveling the analysis to a gene regulatory network instead of focusing on single genes has been suggested to overcome the heterogeneity issue although the majority of the network methods require large datasets. Network methods that are able to function at a single sample level are needed to overcome the heterogeneity and sample size issues. Methods We present a novel network method, Differentially Expressed Regulation Analysis (DERA) that integrates expression data to biological network information at a single sample level. The sample-specific networks are subsequently used to discover samples with similar molecular functions by identification of regulations that are shared between samples or are specific for a subgroup. Results We applied DERA to identify key regulations in triple negative breast cancer (TNBC), which is characterized by lack of estrogen receptor, progesterone receptor and HER2 expression and has poorer prognosis than the other breast cancer subtypes. DERA identified 110 core regulations consisting of 28 disconnected subnetworks for TNBC. These subnetworks are related to oncogenic activity, proliferation, cancer survival, invasiveness and metastasis. Our analysis further revealed 31 regulations specific for TNBC as compared to the other breast cancer subtypes and thus form a basis for understanding TNBC. We also applied DERA to high-grade serous ovarian cancer (HGS-OvCa) data and identified several common regulations between HGS-OvCa and TNBC. The performance of DERA was compared to two pathway analysis methods GSEA and SPIA and our results shows better reproducibility and higher sensitivity in a small sample set. Conclusions We present a novel method called DERA to identify subnetworks that are similarly active for a group of samples. DERA was applied to breast cancer and ovarian cancer data showing our method is able to identify reliable and potentially important regulations with high reproducibility. R package is available at http://csbi.ltdk.helsinki.fi/pub/czliu/DERA/ .
  • Kaur, Sippy; Lotsari, Johanna E; Al-Sohaily, Sam; Warusavitarne, Janindra; Kohonen-Corish, Maija R; Peltomäki, Päivi (BioMed Central, 2015)
    Abstract Background Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Results Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis. Conclusions Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.
  • Kaur, Sippy; Lotsari, Johanna E; Al-Sohaily, Sam; Warusavitarne, Janindra; Kohonen-Corish, Maija R; Peltomäki, Päivi (BioMed Central, 2015)
    Abstract Background Altered expression of microRNAs (miRNAs) commonly accompanies colorectal (CRC) and endometrial carcinoma (EC) development, but the underlying mechanisms and clinicopathological correlations remain to be clarified. We focused on epigenetic mechanisms and aimed to explore if DNA methylation patterns in tumors depend on DNA mismatch repair (MMR) status, sporadic vs. Lynch-associated disease, and geographic origin (Finland vs. Australia). Treatment of cancer cell lines with demethylating agents revealed 109 significantly upregulated miRNAs. Seven met our stringent criteria for possible methylation-sensitive miRNAs and were used to screen patient specimens (205 CRCs and 36 ECs) by methylation-specific multiplex ligation-dependent probe amplification. Results Three miRNAs (129-2, 345, and 132) with low methylation levels in normal tissue and frequent hypermethylation in tumors were of particular interest. Hypermethylation of miR-345 and miR-132 associated with MMR deficiency in CRC regardless of geographic origin, and hypermethylation of miR-132 distinguished sporadic MMR-deficient CRC from Lynch-CRC. Finally, hypermethylation of miRNAs stratified 49 endometrial hyperplasias into low-methylator (simple hyperplasia) and high-methylator groups (complex hyperplasia with or without atypia) and suggested that miR-129-2 methylation in particular could serve as a marker of progression in early endometrial tumorigenesis. Conclusions Our study identifies miR-345 and miR-132 as novel differentially methylated miRNAs in CRC, thereby facilitating sub-classification of CRC and links miR-129-2 methylation to early endometrial tumorigenesis.
  • Zhang, Yanlei; Ning, Feng; Sun, Jianping; Pang, Zengchang; Wang, Xiaoyong; Kapur, Anil; Sintonen, Harri; Qiao, Qing (BioMed Central, 2015)
    Abstract Background Screening for type 2 diabetes helps detect previously unknown diabetes and identify people with pre-diabetes, but the adverse impact of such screening on individuals labelled as pre-diabetes or classified as normal, is less known. In this study the health-related quality of life (HRQoL), depression and lifestyle changes in a rural Chinese population are assessed three years after a screening program. Methods A total of 647 (39.1%) individuals with pre-diabetes and 1009 (60.9%) individuals with normoglycaemia from a population-based diabetes screening program in 2009 were re-examined in 2012–2013. Changes at the end of 3 years in HRQoL, depression, BMI, weight, frequency of physical activity and vegetable intake were assessed. Results In men with normoglycaemia the mean (SD) 15D scores were 0.974 (0.04) at baseline and 0.973 (0.05) at follow-up; and 0.971 (0.05) and 0.966 (0.06) for men with pre-diabetes. In women the scores were 0.973 (0.05) and 0.963 (0.06) for normoglycaemia and 0.959 (0.06) and 0.954 (0.07) for pre-diabetes, respectively. Compared to baseline, the HRQoL was slightly lower at 3 years in all groups but the change was not considered to be clinically important, and was only statistically significant for women with normoglycaemia (p < 0.05). The depression score was slightly elevated in women, but not in men. No significant changes in BMI were noticed, but weight increased slightly in the normoglycemia group (p < 0.05). Screening had a significant positive impact on physical activity and vegetable intake. Conclusions This population-based diabetes screening program generated long-term positive changes toward a healthy lifestyle as measured by physical activity and vegetable intake for all the participants without adverse effects on the HRQoL and depression.
  • Akl, Elie A; Kahale, Lara A; Agarwal, Arnav; Al-Matari, Nada; Ebrahim, Shanil; Alexander, Paul E; Briel, Matthias; Brignardello-Petersen, Romina; Busse, Jason W; Diab, Batoul; Iorio, Alfonso; Kwong, Joey; Li, Ling; Lopes, Luciane C; Mustafa, Reem; Neumann, Ignacio; Tikkinen, Kari AO; Vandvik, Per O; Zhang, Yuqing; Alonso-Coello, Pablo; Guyatt, Gordon (BioMed Central Ltd, 2014)
    Abstract Background There is no consensus on how authors conducting meta-analysis should deal with trial participants with missing outcome data. The objectives of this study are to assess in Cochrane and non-Cochrane systematic reviews: (1) which categories of trial participants the systematic review authors consider as having missing participant data (MPD), (2) how trialists reported on participants with missing outcome data in trials, (3) whether systematic reviewer authors actually dealt with MPD in their meta-analyses of dichotomous outcomes consistently with their reported methods, and (4) the impact of different methods of dealing with MPD on pooled effect estimates in meta-analyses of dichotomous outcomes. Methods/Design We will conduct a methodological study of Cochrane and non-Cochrane systematic reviews. Eligible systematic reviews will include a group-level meta-analysis of a patient-important dichotomous efficacy outcome, with a statistically significant effect estimate. Teams of two reviewers will determine eligibility and subsequently extract information from each eligible systematic review in duplicate and independently, using standardized, pre-piloted forms. The teams will then use a similar process to extract information from the trials included in the meta-analyses of interest. We will assess first which categories of trial participants the systematic reviewers consider as having MPD. Second, we will assess how trialists reported on participants with missing outcome data in trials. Third, we will compare what systematic reviewers report having done, and what they actually did, in dealing with MPD in their meta-analysis. Fourth, we will conduct imputation studies to assess the effects of different methods of dealing with MPD on the pooled effect estimates of meta-analyses. We will specifically calculate for each method (1) the percentage of systematic reviews that lose statistical significance and (2) the mean change of effect estimates across systematic reviews. Discussion The impact of different methods of dealing with MPD on pooled effect estimates will help judge the associated risk of bias in systematic reviews. Our findings will inform recommendations regarding what assumptions for MPD should be used to test the robustness of meta-analytical results.
  • Ritari, Jarmo; Salojärvi, Jarkko; Lahti, Leo; de Vos, Willem M (BioMed Central, 2015)
    Abstract Background Current sequencing technology enables taxonomic profiling of microbial ecosystems at high resolution and depth by using the 16S rRNA gene as a phylogenetic marker. Taxonomic assignation of newly acquired data is based on sequence comparisons with comprehensive reference databases to find consensus taxonomy for representative sequences. Nevertheless, even with well-characterised ecosystems like the human intestinal microbiota it is challenging to assign genus and species level taxonomy to 16S rRNA amplicon reads. A part of the explanation may lie in the sheer size of the search space where competition from a multitude of highly similar sequences may not allow reliable assignation at low taxonomic levels. However, when studying a particular environment such as the human intestine, it can be argued that a reference database comprising only sequences that are native to the environment would be sufficient, effectively reducing the search space. Results We constructed a 16S rRNA gene database based on high-quality sequences specific for human intestinal microbiota, resulting in curated data set consisting of 2473 unique prokaryotic species-like groups and their taxonomic lineages, and compared its performance against the Greengenes and Silva databases. The results showed that regardless of used assignment algorithm, our database improved taxonomic assignation of 16S rRNA sequencing data by enabling significantly higher species and genus level assignation rate while preserving taxonomic diversity and demanding less computational resources. Conclusion The curated human intestinal 16S rRNA gene taxonomic database of about 2500 species-like groups described here provides a practical solution for significantly improved taxonomic assignment for phylogenetic studies of the human intestinal microbiota.
  • Tudor-Locke, Catrine; Barreira, Tiago V; Schuna, John M; Mire, Emily F; Chaput, Jean-Philippe; Fogelholm, Mikael; Hu, Gang; Kuriyan, Rebecca; Kurpad, Anura; Lambert, Estelle V; Maher, Carol; Maia, José; Matsudo, Victor; Olds, Tim; Onywera, Vincent; Sarmiento, Olga L; Standage, Martyn; Tremblay, Mark S; Zhao, Pei; Church, Timothy S; Katzmarzyk, Peter T (BioMed Central, 2015)
    Abstract Background We compared 24-hour waist-worn accelerometer wear time characteristics of 9–11 year old children in the International Study of Childhood Obesity, Lifestyle and the Environment (ISCOLE) to similarly aged U.S. children providing waking-hours waist-worn accelerometer data in the 2003–2006 National Health and Nutrition Examination Survey (NHANES). Methods Valid cases were defined as having ≥4 days with ≥10 hours of waking wear time in a 24-hour period, including one weekend day. Previously published algorithms for extracting total sleep episode time from 24-hour accelerometer data and for identifying wear time (in both the 24-hour and waking-hours protocols) were applied. The number of valid days obtained and a ratio (percent) of valid cases to the number of participants originally wearing an accelerometer were computed for both ISCOLE and NHANES. Given the two surveys’ discrepant sampling designs, wear time (minutes/day, hours/day) from U.S. ISCOLE was compared to NHANES using a meta-analytic approach. Wear time for the 11 additional countries participating in ISCOLE were graphically compared with NHANES. Results 491 U.S. ISCOLE children (9.92±0.03 years of age [M±SE]) and 586 NHANES children (10.43 ± 0.04 years of age) were deemed valid cases. The ratio of valid cases to the number of participants originally wearing an accelerometer was 76.7% in U.S. ISCOLE and 62.6% in NHANES. Wear time averaged 1357.0 ± 4.2 minutes per 24-hour day in ISCOLE. Waking wear time was 884.4 ± 2.2 minutes/day for U.S. ISCOLE children and 822.6 ± 4.3 minutes/day in NHANES children (difference = 61.8 minutes/day, p < 0.001). Wear time characteristics were consistently higher in all ISCOLE study sites compared to the NHANES protocol. Conclusions A 24-hour waist-worn accelerometry protocol implemented in U.S. children produced 22.6 out of 24 hours of possible wear time, and 61.8 more minutes/day of waking wear time than a similarly implemented and processed waking wear time waist-worn accelerometry protocol. Consistent results were obtained internationally. The 24-hour protocol may produce an important increase in wear time compliance that also provides an opportunity to study the total sleep episode time separate and distinct from physical activity and sedentary time detected during waking-hours. Trial registration ClinicalTrials.gov NCT01722500 .
  • Määttä, Suvi; Lehto, Reetta; Nislin, Mari; Ray, Carola; Erkkola, Maijaliisa; Sajaniemi, Nina; Roos, Eva (BioMed Central, 2015)
    Abstract Background Effective interventions that target socioeconomic status (SES) differences to avoid the potential widening of inequalities in health are needed. Children at preschool age is a valuable intervention target since sedentary behaviors, physical activity (PA), dietary behaviors, and sleep habits, jointly called the energy balance-related behaviors (EBRBs), are established in early childhood and tend to persist later in life. The interventions are most effective, when they focus on evidence-based factors. One potential factor associated with EBRBs and SES is children’s stress regulation, which receives special attention in this study. Based on the socioecological approach, the combinations of multiple levels (e.g. individual, environmental, societal) of analysis and diverse methodologies (e.g. surveys, observations, biological measurements) are used to assess the healthfulness of environments (e.g. social, physical, learning, policy) in preschool and family settings. The intervention aimed to diminish SES differences in EBRBs is then conducted in the preschool setting. Methods/design The DAGIS study is divided into two phases. The first phase comprises focus group interviews and a cross-sectional survey. Parents and preschool personnel in low SES neighborhoods participated in interviews about children’s sedentary behaviors, dietary behaviors, and PA in 2014. In the cross-sectional survey beginning in autumn 2015, preschools will be recruited from a random sample of preschools in 3–5 municipalities in Southern Finland. A total of 800 children will wear an accelerometer for seven days. Children’s hair and saliva samples will be taken. Parents and preschool personnel will complete questionnaires on EBRBs, social and physical environments and SES factors. The quality of preschool environment is also observed. In the second phase, an intervention targeting to narrowing SES differences in EBRBs is conducted. The effects of the intervention will be evaluated in randomised controlled trial. The implementation of the intervention will also be evaluated. Conclusion If effective, this unique preschool-based study will be able to narrow the SES differences in preschool children’s EBRBs. This study is anticipated to identify the most important modifiable factors in preschool and family environmental settings associated with children’s EBRBs, especially in children from low SES backgrounds. Trial registration ISRCTN57165350 (January, 8th, 2015).
  • Määttä, Suvi; Lehto, Reetta; Nislin, Mari; Ray, Carola; Erkkola, Maijaliisa; Sajaniemi, Nina; Roos, Eva (BioMed Central, 2015)
    Abstract Background Effective interventions that target socioeconomic status (SES) differences to avoid the potential widening of inequalities in health are needed. Children at preschool age is a valuable intervention target since sedentary behaviors, physical activity (PA), dietary behaviors, and sleep habits, jointly called the energy balance-related behaviors (EBRBs), are established in early childhood and tend to persist later in life. The interventions are most effective, when they focus on evidence-based factors. One potential factor associated with EBRBs and SES is children’s stress regulation, which receives special attention in this study. Based on the socioecological approach, the combinations of multiple levels (e.g. individual, environmental, societal) of analysis and diverse methodologies (e.g. surveys, observations, biological measurements) are used to assess the healthfulness of environments (e.g. social, physical, learning, policy) in preschool and family settings. The intervention aimed to diminish SES differences in EBRBs is then conducted in the preschool setting. Methods/design The DAGIS study is divided into two phases. The first phase comprises focus group interviews and a cross-sectional survey. Parents and preschool personnel in low SES neighborhoods participated in interviews about children’s sedentary behaviors, dietary behaviors, and PA in 2014. In the cross-sectional survey beginning in autumn 2015, preschools will be recruited from a random sample of preschools in 3–5 municipalities in Southern Finland. A total of 800 children will wear an accelerometer for seven days. Children’s hair and saliva samples will be taken. Parents and preschool personnel will complete questionnaires on EBRBs, social and physical environments and SES factors. The quality of preschool environment is also observed. In the second phase, an intervention targeting to narrowing SES differences in EBRBs is conducted. The effects of the intervention will be evaluated in randomised controlled trial. The implementation of the intervention will also be evaluated. Conclusion If effective, this unique preschool-based study will be able to narrow the SES differences in preschool children’s EBRBs. This study is anticipated to identify the most important modifiable factors in preschool and family environmental settings associated with children’s EBRBs, especially in children from low SES backgrounds. Trial registration ISRCTN57165350 (January, 8th, 2015).
  • McAneney, Helen; Tully, Mark A; Hunter, Ruth F; Kouvonen, Anne; Veal, Philip; Stevenson, Michael; Kee, Frank (BioMed Central, 2015)
    Abstract Background It has been argued that though correlated with mental health, mental well-being is a distinct entity. Despite the wealth of literature on mental health, less is known about mental well-being. Mental health is something experienced by individuals, whereas mental well-being can be assessed at the population level. Accordingly it is important to differentiate the individual and population level factors (environmental and social) that could be associated with mental health and well-being, and as people living in deprived areas have a higher prevalence of poor mental health, these relationships should be compared across different levels of neighbourhood deprivation. Methods A cross-sectional representative random sample of 1,209 adults from 62 Super Output Areas (SOAs) in Belfast, Northern Ireland (Feb 2010 – Jan 2011) were recruited in the PARC Study. Interview-administered questionnaires recorded data on socio-demographic characteristics, health-related behaviours, individual social capital, self-rated health, mental health (SF-8) and mental well-being (WEMWBS). Multi-variable linear regression analyses, with inclusion of clustering by SOAs, were used to explore the associations between individual and perceived community characteristics and mental health and mental well-being, and to investigate how these associations differed by the level of neighbourhood deprivation. Results Thirty-eight and 30 % of variability in the measures of mental well-being and mental health, respectively, could be explained by individual factors and the perceived community characteristics. In the total sample and stratified by neighbourhood deprivation, age, marital status and self-rated health were associated with both mental health and well-being, with the ‘social connections’ and local area satisfaction elements of social capital also emerging as explanatory variables. An increase of +1 in EQ-5D-3 L was associated with +1SD of the population mean in both mental health and well-being. Similarly, a change from ‘very dissatisfied’ to ‘very satisfied’ for local area satisfaction would result in +8.75 for mental well-being, but only in the more affluent of areas. Conclusions Self-rated health was associated with both mental health and mental well-being. Of the individual social capital explanatory variables, ‘social connections’ was more important for mental well-being. Although similarities in the explanatory variables of mental health and mental well-being exist, socio-ecological interventions designed to improve them may not have equivalent impacts in rich and poor neighbourhoods.
  • Eggeling, Ralf; Roos, Teemu; Myllymäki, Petri; Grosse, Ivo (BioMed Central, 2015)
    Abstract Background Statistical modeling of transcription factor binding sites is one of the classical fields in bioinformatics. The position weight matrix (PWM) model, which assumes statistical independence among all nucleotides in a binding site, used to be the standard model for this task for more than three decades but its simple assumptions are increasingly put into question. Recent high-throughput sequencing methods have provided data sets of sufficient size and quality for studying the benefits of more complex models. However, learning more complex models typically entails the danger of overfitting, and while model classes that dynamically adapt the model complexity to data have been developed, effective model selection is to date only possible for fully observable data, but not, e.g., within de novo motif discovery. Results To address this issue, we propose a stochastic algorithm for performing robust model selection in a latent variable setting. This algorithm yields a solution without relying on hyperparameter-tuning via massive cross-validation or other computationally expensive resampling techniques. Using this algorithm for learning inhomogeneous parsimonious Markov models, we study the degree of putative higher-order intra-motif dependencies for transcription factor binding sites inferred via de novo motif discovery from ChIP-seq data. We find that intra-motif dependencies are prevalent and not limited to first-order dependencies among directly adjacent nucleotides, but that second-order models appear to be the significantly better choice. Conclusions The traditional PWM model appears to be indeed insufficient to infer realistic sequence motifs, as it is on average outperformed by more complex models that take into account intra-motif dependencies. Moreover, using such models together with an appropriate model selection procedure does not lead to a significant performance loss in comparison with the PWM model for any of the studied transcription factors. Hence, we find it worthwhile to recommend that any modern motif discovery algorithm should attempt to take into account intra-motif dependencies.
  • Mikonranta, Lauri; Mappes, Johanna; Kaukoniitty, Minna; Freitak, Dalial (BioMed Central Ltd, 2014)
    Abstract Background Previous exposure to a pathogen can help organisms cope with recurring infection. This is widely recognised in vertebrates, but increasing occasions are also being reported in invertebrates where this phenomenon is referred to as immune priming. However, the mechanisms that allow acquired pathogen resistance in insects remain largely unknown. Results We studied the priming of bacterial resistance in the larvae of the tiger moth, Parasemia plantaginis using two gram-negative bacteria, a pathogenic Serratia marcescens and a non-pathogenic control, Escherichia coli. A sublethal oral dose of S. marcescens provided the larvae with effective protection against an otherwise lethal septic infection with the same pathogen five days later. At the same time, we assessed three anti-bacterial defence mechanisms from the larvae that had been primarily exposed to the bacteria via contaminated host plant. Results showed that S. marcescens had induced a higher amount of reactive oxygen species (ROS) in the larval haemolymph, possibly protecting the host from the recurring infection. Conclusions Our study supports the growing evidence of immune priming in insects. It shows that activation of the protective mechanism requires a specific induction, rather than a sheer exposure to any gram-negative bacteria. The findings indicate that systemic pathogen recognition happens via the gut, and suggest that persistent loitering of immune elicitors or anti-microbial molecules are a possible mechanism for the observed prophylaxis. The self-harming effects of ROS molecules are well known, which indicates a potential cost of increased resistance. Together these findings could have important implications on the ecological and epidemiological processes affecting insect and pathogen populations.
  • Laurila, Kirsti; Autio, Reija; Kong, Lingjia; Närvä, Elisa; Hussein, Samer; Otonkoski, Timo; Lahesmaa, Riitta; Lähdesmäki, Harri (BioMed Central Ltd, 2014)
    Abstract Background Human genomic variations, including single nucleotide polymorphisms (SNPs) and copy number variations (CNVs), are associated with several phenotypic traits varying from mild features to hereditary diseases. Several genome-wide studies have reported genomic variants that correlate with gene expression levels in various tissue and cell types. Results We studied human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) measuring the SNPs and CNVs with Affymetrix SNP 6 microarrays and expression values with Affymetrix Exon microarrays. We computed the linear relationships between SNPs and expression levels of exons, transcripts and genes, and the associations between gene CNVs and gene expression levels. Further, for a few of the resulted genes, the expression value was associated with both CNVs and SNPs. Our results revealed altogether 217 genes and 584 SNPs whose genomic alterations affect the transcriptome in the same cells. We analyzed the enriched pathways and gene ontologies within these groups of genes, and found out that the terms related to alternative splicing and development were enriched. Conclusions Our results revealed that in the human pluripotent stem cells, the expression values of several genes, transcripts and exons were affected due to the genomic variation.
  • Sumanen, Hilla; Pietiläinen, Olli; Lahti, Jouni; Lahelma, Eero; Rahkonen, Ossi (BioMed Central, 2015)
    Abstract Background A low socioeconomic position (SEP) is consistently associated with ill health, sickness absence (SA) and permanent disability, but studies among young employees are lacking. We examined the interrelationships between education, occupational class and income as determinants of SA among 25-34-year-old employees. We also examined, whether the association between SEP and SA varied over time in 2002–2007 and 2008–2013. Methods The analyses covered young, 25-34-year-old women and men employed by the City of Helsinki over the time periods 2002–2007 and 2008–2013. Four-level education and occupational class classifications were used, as well as income quartiles. The outcome measure was the number of annual SA days. Results Education had the strongest and most consistent independent association with SA among women and men in both periods under study. Occupational class had weaker independent and less consistent association with SA. Income had an independent association with SA, which strengthened over time among the men. The interrelationships between the SEP indicators and SA were partly explained by prior or mediated through subsequent SEP indicators. Socioeconomic differences followed only partially a gradient for occupational class and also for income among men. Conclusions Preventive measures to reduce the risk of SA should be considered, especially among young employees with a basic or lower-secondary education.
  • Sumanen, Hilla; Pietiläinen, Olli; Lahti, Jouni; Lahelma, Eero; Rahkonen, Ossi (BioMed Central, 2015)
    Abstract Background A low socioeconomic position (SEP) is consistently associated with ill health, sickness absence (SA) and permanent disability, but studies among young employees are lacking. We examined the interrelationships between education, occupational class and income as determinants of SA among 25-34-year-old employees. We also examined, whether the association between SEP and SA varied over time in 2002–2007 and 2008–2013. Methods The analyses covered young, 25-34-year-old women and men employed by the City of Helsinki over the time periods 2002–2007 and 2008–2013. Four-level education and occupational class classifications were used, as well as income quartiles. The outcome measure was the number of annual SA days. Results Education had the strongest and most consistent independent association with SA among women and men in both periods under study. Occupational class had weaker independent and less consistent association with SA. Income had an independent association with SA, which strengthened over time among the men. The interrelationships between the SEP indicators and SA were partly explained by prior or mediated through subsequent SEP indicators. Socioeconomic differences followed only partially a gradient for occupational class and also for income among men. Conclusions Preventive measures to reduce the risk of SA should be considered, especially among young employees with a basic or lower-secondary education.
  • Lappalainen, Anu K; Vaittinen, Elina; Junnila, Jouni; Laitinen-Vapaavuori, Outi (BioMed Central Ltd, 2014)
    Abstract Background Intervertebral disc disease (IDD) is a very common neurological disease, Dachshunds being the breed most often affected. In this breed, IDD has a hereditary background and is associated with intervertebral disc calcification (IDC), an indicator of severe intervertebral disc degeneration. In Finland, spinal radiography is used, when screening for IDC before breeding Dachshunds. We evaluated the association between IDC and IDD in Finnish Dachshunds radiographically screened for IDC. A questionnaire was sent to owners of 193 radiographically screened Dachshunds aged at least ten years. Clinical signs indicative of IDD were compared with IDC grade (grade 0&#8201;=&#8201;no calcifications, grade 1&#8201;=&#8201;1 &#8211; 2 calcifications, grade 2&#8201;=&#8201;3 &#8211; 4 calcifications and grade 3&#8201;=&#8201;5 or more calcifications) and with age at the time of the radiographic examination. The diagnosis of IDD was confirmed by a veterinarian. Results IDD was common in the study population with 31% of dogs being affected. IDD and IDC were clearly connected (P&#8201;&lt;&#8201;0.001); IDD was rare in dogs with no calcifications (grade 0) and common in dogs with severe IDC (grade 3). The IDC grade was strongly positively associated with frequency of back pain periods (P&#8201;&lt;&#8201;0.001), and dogs with IDC grade 3 had frequent periods of pain. Reluctance to jump onto a sofa had a strong positive association with back pain. No association existed between age of the dog at the time of the radiographic examination and clinical signs indicative of IDD. Conclusions Radiographically detected IDC and IDD are common in Finnish Dachshunds and are strongly associated with one another. Spinal radiography is an appropriate screening tool for breeders attempting to diminish IDC and IDD in Dachshunds. A breeding program that screens dogs and selects against IDC can be expected to reduce the occurrence of IDD in future. Twenty-four to 48&#160;months of age is a suitable age for screening.
  • Maltamo, Matti; Pesonen, Annukka; Korhonen, Lauri; Kouki, Jari; Vehmas, Mikko; Eerikäinen, Kalle (Beijing Forestry University, 2015)
    Abstract Background The occurrence of aspen trees increases the conservation value of mature conifer dominated forests. Aspens typically occur as scattered individuals among major tree species, and therefore the inventory of aspens is challenging. Methods We characterized aspen populations in a boreal nature reserve using diameter distribution, spatial pattern, and forest attributes: volume, number of aspens, number of large aspen stems and basal area median diameter. The data were collected from three separate forest stands in Koli National Park, eastern Finland. At each site, we measured breast height diameter and coordinates of each aspen. The comparison of inventory methods of aspens within the three stands was based on simulations with mapped field data. We mimicked stand level inventory by locating varying numbers of fixed area circular plots both systematically and randomly within the stands. Additionally, we also tested if the use of airborne laser scanning (ALS) data as auxiliary information would improve the accuracy of the stand level inventory by applying the probability proportional to size sampling to assist the selection of field plot locations. Results The results showed that aspens were always clustered, and the diameter distributions indicated different stand structures in the three investigated forest stands. The reliability of the volume and number of large aspen trees varied from relative root mean square error figures above 50% with fewer sample plots (5–10) to values of 25%–50% with 10 or more sample plots. Stand level inventory estimates were also able to detect spatial pattern and the shape of the diameter distribution. In addition, ALS-based auxiliary information could be useful in guiding the inventories, but caution should be used when applying the ALS-supported inventory technique. Conclusions This study characterized European aspen populations for the purposes of monitoring and management of boreal conservation areas. Our results suggest that if the number of sample plots is adequate, i.e. 10 or more stand level inventory will provide accurate enough forest attributes estimates in conservation areas (minimum accuracy requirement of RMSE% is 20%–50%). Even for the more ecologically valuable attributes, such as diameter distribution, spatial pattern and large aspens, the estimates are acceptable for conservation purposes.