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1.  Impact of prior specifications in ashrinkage-inducing Bayesian model for quantitative trait mapping and genomic prediction 
In quantitative trait mapping and genomic prediction, Bayesian variable selection methods have gained popularity in conjunction with the increase in marker data and computational resources. Whereas shrinkage-inducing methods are common tools in genomic prediction, rigorous decision making in mapping studies using such models is not well established and the robustness of posterior results is subject to misspecified assumptions because of weak biological prior evidence.
Here, we evaluate the impact of prior specifications in a shrinkage-based Bayesian variable selection method which is based on a mixture of uniform priors applied to genetic marker effects that we presented in a previous study. Unlike most other shrinkage approaches, the use of a mixture of uniform priors provides a coherent framework for inference based on Bayes factors. To evaluate the robustness of genetic association under varying prior specifications, Bayes factors are compared as signals of positive marker association, whereas genomic estimated breeding values are considered for genomic selection. The impact of specific prior specifications is reduced by calculation of combined estimates from multiple specifications. A Gibbs sampler is used to perform Markov chain Monte Carlo estimation (MCMC) and a generalized expectation-maximization algorithm as a faster alternative for maximum a posteriori point estimation. The performance of the method is evaluated by using two publicly available data examples: the simulated QTLMAS XII data set and a real data set from a population of pigs.
Combined estimates of Bayes factors were very successful in identifying quantitative trait loci, and the ranking of Bayes factors was fairly stable among markers with positive signals of association under varying prior assumptions, but their magnitudes varied considerably. Genomic estimated breeding values using the mixture of uniform priors compared well to other approaches for both data sets and loss of accuracy with the generalized expectation-maximization algorithm was small as compared to that with MCMC.
Since no error-free method to specify priors is available for complex biological phenomena, exploring a wide variety of prior specifications and combining results provides some solution to this problem. For this purpose, the mixture of uniform priors approach is especially suitable, because it comprises a wide and flexible family of distributions and computationally intensive estimation can be carried out in a reasonable amount of time.
PMCID: PMC3750442  PMID: 23834140
2.  Associations between Variation in CHRNA5-CHRNA3-CHRNB4, Body Mass Index and Blood Pressure in the Northern Finland Birth Cohort 1966 
PLoS ONE  2012;7(9):e46557.
The CHRNA5-CHRNA3-CHRNB4 gene cluster on 15q25 has consistently been associated with smoking quantity, nicotine dependence and lung cancer. Recent research also points towards its involvement in cardiovascular homeostasis, but studies in large human samples are lacking, especially on the role of the gene cluster in blood pressure regulation.
Methodology/Principal Findings
We studied the associations between 18 single nucleotide polymorphisms (SNPs) in CHRNA5-CHRNA3-CHRNB4 and systolic blood pressure (SBP), diastolic blood pressure (DBP), and body mass index (BMI) in 5402 young adults from the Northern Finland Birth Cohort 1966. We observed some evidence for associations between two SNPs and SBP and between six SNPs and BMI; the evidence for associations with DBP was weaker. The associations with the three phenotypes were driven by different loci with low linkage disequilibrium with each other. The associations appeared more pronounced in smokers, such that the smoking-increasing alleles would predict lower SBP and BMI. Each additional copy of the rs1948 G-allele and the rs950776 A-allele reduced SBP on average by −1.21 (95% CI −2.01, −0.40) mmHg in smokers. The variants associated with BMI included rs2036534, rs6495309, rs1996371, rs6495314, rs4887077 and rs11638372 and had an average effect size of −0.38 (−0.68, −0.08) kg/m2 per an additional copy of the risk allele in smokers. Formal assessments of interactions provided weaker support for these findings, especially after adjustment for multiple testing.
Variation at 15q25 appears to interact with smoking status in influencing SBP and BMI. The genetic loci associated with SBP were in low linkage disequilibrium with those associated with BMI suggesting that the gene cluster might regulate SBP through biological mechanisms that partly differ from those regulating BMI. Further studies in larger samples are needed for more precise evaluation of the possible interactions, and to understand the mechanisms behind.
PMCID: PMC3459914  PMID: 23029550
3.  Self‐reported health problems and sickness absence in different age groups predominantly engaged in physical work 
To study the associations between self‐reported health problems and sickness absence from work.
The results of a questionnaire survey were combined with archival data of sickness absence of 1341 employees (88% males; 62% blue‐collar) in the construction, service and maintenance work within one corporation in Finland. Sex, age and occupational grading were controlled as confounders. A zero‐inflated negative binomial (ZINB) regression model was used in the statistical analysis of sickness absence data.
The prevalence of self‐reported health problems increased with age, from 23% in 18–30‐year‐olds to 54% in 55–61‐year‐olds. However, in those aged 18–30 years, 71% had been absent from work and in those aged 55–61 years this proportion was 53%. When health problems and occupational grading were accounted for in the ZINB model, age as such was not associated with the number of days on sick leave, but the young workers still had higher propensity for (any) sickness absence than the old. Self‐rated future working ability and musculoskeletal impairment were strong determinants of sickness absence. Among those susceptible to taking sick leave, the estimated mean number of absence days increased by 14% for each rise of 1 unit of the impairment score (scale 0–10).
Young subjects had surprisingly high probability for sickness absence although they reported better health than their older colleagues. A higher total count of absence days was found among subjects reporting health problems and poorer working ability, regardless of age, sex and occupational grade. These findings have implications for both management and the healthcare system in the prevention of work disability.
PMCID: PMC2078413  PMID: 17303674
4.  Life-Course Analysis of a Fat Mass and Obesity-Associated (FTO) Gene Variant and Body Mass Index in the Northern Finland Birth Cohort 1966 Using Structural Equation Modeling 
American Journal of Epidemiology  2010;172(6):653-665.
The association between variation in the fat mass and obesity-associated (FTO) gene and adulthood body mass index (BMI; weight (kg)/height (m)2) is well-replicated. More thorough analyses utilizing phenotypic data over the life course may deepen our understanding of the development of BMI and thus help in the prevention of obesity. The authors used a structural equation modeling approach to explore the network of variables associated with BMI from the prenatal period to age 31 years (1965–1997) in 4,435 subjects from the Northern Finland Birth Cohort 1966. The use of structural equation modeling permitted the easy inclusion of variables with missing values in the analyses without separate imputation steps, as well as differentiation between direct and indirect effects. There was an association between the FTO single nucleotide polymorphism rs9939609 and BMI at age 31 years that persisted after controlling for several relevant factors during the life course. The total effect of the FTO variant on adult BMI was mostly composed of the direct effect, but a notable part was also arising indirectly via its effects on earlier BMI development. In addition to well-established genetic determinants, many life-course factors such as physical activity, in spite of not showing mediation or interaction, had a strong independent effect on BMI.
PMCID: PMC2938267  PMID: 20702506
body mass index; molecular epidemiology; structural equation model
5.  One tissue, two fates: different roles of megagametophyte cells during Scots pine embryogenesis 
Journal of Experimental Botany  2009;60(4):1375-1386.
In the Scots pine (Pinus sylvestris L.) seed, embryos grow and develop within the corrosion cavity of the megagametophyte, a maternally derived haploid tissue, which houses the majority of the storage reserves of the seed. In the present study, histochemical methods and quantification of the expression levels of the programmed cell death (PCD) and DNA repair processes related genes (MCA, TAT-D, RAD51, KU80, and LIG) were used to investigate the physiological events occurring in the megagametophyte tissue during embryo development. It was found that the megagametophyte was viable from the early phases of embryo development until the early germination of mature seeds. However, the megagametophyte cells in the narrow embryo surrounding region (ESR) were destroyed by cell death with morphologically necrotic features. Their cell wall, plasma membrane, and nuclear envelope broke down with the release of cell debris and nucleic acids into the corrosion cavity. The occurrence of necrotic-like cell death in gymnosperm embryogenesis provides a favourable model for the study of developmental cell death with necrotic-like morphology and suggests that the mechanism underlying necrotic cell death is evolutionary conserved.
PMCID: PMC2657542  PMID: 19246593
Conifer; developmental cell death; embryogenesis; megagametophyte; necrotic cell death; seed development

Results 1-6 (6)