text:
Childhood Neglect and Abuse Can Have Long-Term Economic Consequences
People who suffer neglect and abuse in childhood are much more likely to have time off work due to long-term sickness and are less likely to own their own homes when they reach middle age, according to a new study.
Published in the journal Pediatrics and undertaken as part of the Public Health Research Consortium, the study showed that the potential socioeconomic impact of child neglect and abuse may persist for decades.
Researchers at University College London found that neglected children often had worse reading and mathematics skills in adolescence than their peers, which could hamper their ability to find work and progress in the job market. These factors did not explain the poorer standard of living for those reporting child abuse, the researchers noted.
For the study, the research team followed 8,076 people from birth in 1958 until the age of 50, examining key socioeconomic indicators.
A person's economic circumstances at the age of 50 are important because this is close to peak earning capacity in the U.K., the researchers explained. Poor living standards at this age can signal hardship and associated ill health during old age.
The research found adults who had been neglected in childhood were approximately 70 percent more likely to have time off work due to long-term sickness and not own their home at 50 years, compared to their peers who had not suffered from child abuse and neglect.
Also, the risk of a poor outcome was greatest for people experiencing multiple types of child maltreatment. For example those experiencing two or more types of child maltreatment, such as child neglect and physical abuse, had more than double the risk of long-term sickness absence from work, compared to those experiencing no maltreatment.
"Our findings suggest that maltreated children grow up to face socioeconomic disadvantage. This is important because such disadvantage could, in turn, influence the health of individuals affected and also that of their children," said Dr. Snehal Pinto Pereira of the UCL Great Ormond Street Institute of Child Health, who led the research.
"As well as highlighting the importance of prevention of maltreatment in childhood, our research identified poor reading and mathematics skills as a likely connecting factor from child neglect to poor adult outcomes. This suggests that action is needed to improve and support these abilities in neglected children."
Source: University College London
Wood, J. (2018). Childhood Neglect and Abuse Can Have Long-Term Economic Consequences. Psych Central. Retrieved on October 31, 2020, from https://psychcentral.com/news/2016/12/20/childhood-neglect-and-abuse-have-long-term-economic-consequences/114072.html
Last reviewed: By a member of our scientific advisory board on 8 Aug 2018
Published on Psych Central.com. All rights reserved.


text:
Posted Sept. 15, 2020, 3:38 p.m. by Captain Alexander Cochrane (Commanding Officer) (James Sinclair)
Posted by Lieutenant Commander Zef Rollo (Counselor) in Captain's Quarters - Side Sim
Posted by Captain Alexander Cochrane (Commanding Officer) in Captain's Quarters - Side Sim
Posted by Lieutenant Commander Zef Rollo (Counselor) in Captain's Quarters - Side Sim
Posted by… suppressed (5) by the Post Ghost! 👻
It had been five days since Zef had her first meeting with Kalig Marrov and Captain Cochrane. The meeting in which the Bajeen male announced a marital claim to the counselor by way of his dead brother. After Cochrane sent him back to his ship, the Kestra, Zef returned to her quarters and sent a message to Ganro Fleg, her friend who still lived and thrived on Baj along with his family. She'd asked him to look in to the matter—to find out if such a law existed and if there was any chance at all that she might have to consider Kalig's claim on her.
It was all very involved. In normal circumstances, she wouldn't have given it any thought, but keeping tradition and staying involved with Bajeen life was something her mother, Anara, begged her to keep alive in her life. That was the only reason she'd taken time to find out if Marrov's claim was true or just something made up to put her off guard.
As it turned out, Ganro worked tirelessly to investigate the old laws that covered that particular aspect of spousal responsibility with siblings of a mated pair when there were not children from the joining. That evening when she'd returned from her day of counseling members of the crew, there was a message waiting for her when she entered her quarters.
Instead of running directly to the computer, Zef took a few minutes to change out of her uniform into a lavender colored, casual gown. The strappy top and loose body, and the soft material and decorative lace at the hem, helped her feel 'normal' and individual—unlike her uniform did. Grabbing a glass of wine before seating herself at the desk, Zef ran a hand back through her long, white hair and sighed loudly. The next moment or two could change her life…
—Zef (cue the mysterious music…)
Ten minutes later, the message had played out, her wine glass was empty and her heart was lighter. She had a thoughtful look on her face as she walked to the replicator to refill her glass. She took it to the sofa and got comfortable. As she sipped the fruity wine, her mind swirled with how to handle the next bit. Kalig had to be informed that she wasn't going anywhere with him—that might make his real purpose for showing up at the places she had been assigned, come to light. Truthfully, she didn't want another thing to do with the Marrov family, not even a short communique with her ex brother in law. However, she could tell the Captain what was going on. It was after his duty shift so Zef was loathe to bother him, but he had said he wanted to know the minute she heard something.
Downing the last mouthful of golden liquid in the glass, she rose from the couch and headed to the vanity in the bathroom to check her appearance. The wine coursed through her system, relaxing muscles and mental barriers as she ran a brush through her loose hair and pulled it all over one shoulder. When she found herself placing a dot of softly scented perfume on the pulse points of her neck, she shook her head at her reflection. "As if. He already told you he just wanted to be friends." She was fine with the idea of staying platonic with Cochrane most of the time, but there were moments when desire for him caused her some discomfort. =/\=Computer, location of the Captain?=/\=
=/\=Captain Cochrane is currently in his quarters.=/\=
Flinging off the bothersome thoughts, Zef slipped her feet into simple sandals and made her way to deck 2. There were only two sets of quarters on that level, the CO's and the XO's. Making sure she took the correct turn, she arrived outside of Cochrane's rooms. When she reached for the chime and noticed her hand wasn't shaking at all, she smiled just a bit. Best to try and keep it together for the short meeting ahead. With that in mind, the counselor activated the chime to let him know someone was at his door.
There was a long pause and then the door slid open. Cochrane stood in the doorway in a pair of gray sweatpants and a blue zippered hoodie that was partly open, exposing bare skin. He wore an obviously hesitant expression as the doors opened as he wasn't expecting anyone. But when he saw the Counselor, he smiled and said "Ah, Counselor. Please, please… come in." and stepped aside and held his right arm out to invite her inside.
The Captain's quarters were comfortable and spacious, befitting the Commanding Officer of one of the larger ships in Star Fleet. The room was set up with the doorway in the middle of a large living space. A couch sat below the large window that made up the wall opposite the door, and a low but very sturdy-looking table sat in front if it flanked by large chairs on either side. To the right of the door was a desk set so that a person sitting there would have their back in the far right corner of the room which, in turn, was flanked by bookcases similar to the ones in the Captain's Ready Room. To the left of the door was a small kitchen with a tall table and chairs sat on the door side of the kitchen island which held the sink. Past the sink was a cooking surface and a replicator and cabinets. In the far left corner near the window sat an assortment of musical instruments on stands: a guitar, bass guitar, upright bass, and a saxophone. In the far opposite corner was a small piano and a cello.
There were doors on either end of the room, the one the right being closed but the one on the left was open and the darkened bedroom could be seen through the doorway.
As she entered he stepped away and let the door slide closed and said "What can I do for you, Commander? Any word on the issue at hand?" and he moved into the kitchen area and opened a cabinet. "Something to drink?" he asked politely.
Cochrane, CO
It was her first look at his quarters. The tidiness pleased her—Zef had a problem with messes. It also had a masculine feel with color choices and decor. "This is a nice space you have." She walked farther into the room and did a 360 to take in the whole thing. Her glance lingered for an extra second on the bedroom doorway, wondering what choices he'd made in there.
Not expecting a drink, she smiled. Might as well continue with the relaxed mood she was currently enjoying. "A glass of white wine, please. Something fruity, if you have it." Feeling more at home than expected, she kicked off her sandals close to the table in front of the couch and enjoyed the feel of expensive carpet on her bare feet as she walked to the view ports that lined the far wall.
"Yes, there is news. I just heard from Ganro."
Cochrane watched her out of the corner of his eye and when she said she had word, he smiled. "And as you are not storming in here, hands flying and on the verge of committing murder, I take it you have good news then?" He walked to a long, narrow cabinet next to the replicator and opened it: a wine cabinet. He ran his hand down the necks of the various bottle until he muttered "Ah, yes." and removed a light blue bottle with a dark green wax seal across the top. He set it on the cooking surface and tapped a few commands and the wine chilled almost instantly. He opened the bottle by cracking the wax seal with a wire that pulled the top free, and then drew the cork out. Grabbing two glasses, he carried them in one hand and the bottle in the other and came to the low table made of deep, dark wood. Closer view would ahow it was carved with scowling, toothy, almost demonic faces around the tops edge.
Setting the glasses down he poured them each a glass and then took a seat in one of the overstuffed chairs. "Do tell, Commander. And please, have a seat. Make yourself comfortable."
Cochrane, CO
She watched as he moved around the room, enjoying the view. It was fine as long as she kept silent about it. Zef folded herself into the corner of the couch nearest the chair the Captain sat in. She didn't sink completely into it as that wouldn't allow her to reach the table where her wine sat, so she sat forward and crossed her legs, the dainty pink polish on her toes very evident on her pale, bare feet.
"Ganro's a good friend. He spent many hours pouring through old law journals for me. The good news is that there was a law about mating into a family and being passed to another brother after the death of a spouse—if there were no living children from the original union, but that idea was done away with over 400 years ago." She tasted the wine. "Mmmmm, very nice." As she gazed at Cochrane and smiled, her eyes lingered on the open neck of the hoodie he wore. It was a double entendre, yes, but he didn't know that and she was feeling a little bit dangerous.
He nodded as she complimented the wine. "Its a Vulcan wine. My mother and father have a vineyard there." Whether or not he caught her lingering gaze was not apparent.
"So your wayward brother-in-law has no legal legs to stand on… good. One less complication to ha e to contend with. But now the question becomes what do we do about him to keep him from troubling you in the future."
Cochrane, CO
Zef chuckled. "There's no way to foresee what Kalig might come up with, but as far as I know, I'm not tied to him or his family at all now." Another swallow of wine as she thought about possibilities. "He can't have really been after me because of an old law, but since his claim I've done some thinking." She didn't like what she'd come up with but it did answer the big question.
Leaning a little more towards Alex, the Bajeen prepared to tell him something very personal. "I'm not anything special here in Star Fleet, but back home…my coloring, or lack of coloring, makes me fairly unique. We are called Azj'don ta—white ones." She looked down at her feet and wiggled the pastel painted toes, taking note of the pale, pale skin.
"I've heard of a few instances where others like me went missing. No trace was ever found… I think men like Kalig might be selling other Azj'don ta to the highest bidders. He IS a mercenary, after all." What kind of life would those Bajeen have?
Once again, her blue-gray eyes found the Captain's. "Its a horrible thought, but it makes sense of all that's happened."
Cochrane scowled and his jaw clenched. "Is albinism that uncommon that your very own people would sell you into slavery to the rich and powerful? Why not just pay for the genetic modification?" The question was logical… the tone was barely suppressed anger. Few things immediately set off Alex's temper… the practice of slavery was two of those things.
Cochrane, CO
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text:
Original Research ARTICLE
Evaluation of genetic risk score models in the presence of interaction and linkage disequilibrium
- Department of Statistics, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
In the area of genetic epidemiology, genetic risk predictive modeling is becoming an important area of translational success. As an increasing number of genetic variants are successfully discovered, the use of multiple genetic variants in constructing a genetic risk score (GRS) for modeling has been widely applied using a variety of approaches. Previously, we compared the performance of a simple, additive GRS with weighted GRS approaches, but our initial simulation experiment assumed very simple models without many of the complications found in real genetic studies. In particular, interactions between variants and linkage disequilibrium (LD) (indirect mapping) remain important and challenging problems for GRS modeling. In the present study, we applied two simulation strategies to mimic various types of epistasis to evaluate their impact on the performance of the GRS models. We simulated a range of models demonstrating statistical interaction and linkage disequilibrium. Three genetic risk models were compared in terms of power, type I error, C-statistic and AIC, including a simple count GRS (SC-GRS), an odds ratio weighted GRS (OR-GRS) and an explained variance weighted GRS (EV-GRS). Simulation factors of interest included allele frequencies, effect sizes, strengths of interaction, degrees of LD and heritability. We extensively examined the extent to how these interactions could influence the performance of genetic risk models. Our results show that the weighted methods outperform simple count method in general even if interaction or LD is present, with well controlled type I error.
In recent years, Genome-Wide Association Studies (GWAS) and candidate gene studies have identified a large number of genetic variants with varying effect size that are associated with complex diseases (McCarthy et al., 2008) and drug response/pharmacogenomic traits (Ritchie, 2012). This identification of causal and/or associated variants provides new opportunities to develop more personalized approaches to disease prediction and prevention. One popular approach for incorporating identified genetic variants is by constructing a genetic risk score (GRS) for modeling using a variety of approaches, such as an additive simple count and weighted GRS (Carayol et al., 2010; Paynter et al., 2010). The applicability of these cumulative risk scores as predictive models for disease has been proposed and brought anecdotal successes in the real genetic studies (Hess et al., 2006; Meigs et al., 2008; Klein et al., 2009; Manolio, 2010). While several approaches have been implemented successfully and become widely applied in real data analyses, these risk score models have not been thoroughly evaluated, particularly in complex scenarios.
Previously, we compared the performance of a simple, additive GRS with weighted GRS approaches in a wide range of simulation scenarios. Our initial findings show that a weighted method involving both the odds ratio and allele frequency of variants robustly outperforms other GRS models in general (Che and Motsinger-Reif, 2012). However, we recognized that our simulation experiment assumed very simple models without many of the complications found in real genetic studies. In particular, interactions between variants in predicting disease risk and linkage disequilibrium (LD) (indirect correlation between markers) remain important and challenging problems (Winham et al., 2012). When moving from variant discovery to validation and prediction, such complex architecture may bring more challenges. Therefore, a more comprehensive exploration of the consequence of complex etiology and multi-locus correlation on risk modeling is becoming a priority. Although the primary goal of GRS is beyond the initial detection of risk alleles, and typically only involves variants with previously established associations, ignoring interactions may largely limit the success of risk prediction model for complex disease and pharmacogenomic studies.
Epistasis or gene-gene interaction has become a hot topic in complex disease genetics recently. In the previous literature, discussion of epistasis has been considerably confused by differing definitions as well as by applying the same terminology to quite different concepts. In essence, epistasis refers to departure from "independence" of the effects of multiple loci in the way that they combine to cause disease (Cordell, 2002). From a statistical point of view, epistasis represents departure from additivity in a mathematical model that describes the relationship between multiple variants and disease outcome in the population (Cordell, 2002, 2009; Pattin et al., 2009). In contrast, we also simulated models that exhibit correlation between loci—representing linkage disequilibrium (LD) (Lunetta, 2008). Linkage disequilibrium refers to the non-random association of alleles at two or more loci in a population (Shifman et al., 2003; Lunetta, 2008).
In the current study, we explicitly compared the performance of three genetic risk score approaches to detect the true risk model in the presence of interaction and LD, including a simple count (SC-), an odds ratio weighted (OR-) and an explained variance weighted (EV-) genetic risk score method. We employed two simulation strategies to represent (1) epistasis (gene-gene interaction effects on the phenotype) and (2) linkage disequilibrium. The effect sizes and allele frequencies were considered as important factors to evaluate the role of weights in the GRS construction. We also addressed the relationship among effect size, allele frequency, interaction effect, heritability and the predictive power for the GRS models. The main goal of this study was to explore the relationship between the degree of interaction and the performance of genetic risk scores in model prediction in a wide range of scenarios, which may in turn help guide the application of GRS in risk prediction.
Genetic Risk Score Models
In the present study, GRS models were evaluated for single nucleotide polymorphism (SNP) data only. However, it could be easily generalized to other genetic variants or risk factors. It should be noted that we choose SNPs in the GRS construction based on either the previous knowledge of the disease predisposition or the data at hand. Several promising approaches, such as random forests (Winham et al., 2012) and statistical epistasis networks (Hu et al., 2011), were developed to characterize genetic interactions. An evaluation of methods for the identification and selection of risk variants with interaction are beyond the primary goal of the GRS models as implemented here. In the current study, we assume the associated SNPs have been discovered prior to GRS modeling.
Three representative GRS methods were compared in this study, including SC-, OR- and EV-GRS. As implemented in a previous study, a very simple main effect and additive genetic model was assumed in the risk modeling (Che and Motsinger-Reif, 2012). Let D denote the binary phenotype value, where D = 1 represent case and D = 0 represent control. G is a vector of genotype combinations across all genetic loci. Gi is the number of the risk alleles for the i-th SNP. α is an intercept and β measures the overall effect of the genetic risk score. All parameters were estimated under a logistic regression model without any interaction term (Che and Motsinger-Reif, 2012).
Simple count GRS (SC-GRS)
This simple count score model sums up all risk alleles over all loci as a summary score. No prior knowledge is needed. It is relatively simple and thus is in wide application in the current literature (Paynter et al., 2010).
Odds ratio weighted GRS (OR-GRS)
This weighted summary score takes into account the fact that effect sizes among SNPs vary. In general, log per-allele odds ratio from meta-analysis or from other independent data is considered as a reasonable weight to apply to each SNP (Talmud et al., 2010). A rescaled score is utilized since it is more directly comparable to the unweighted score.
Explained variance weighted GRS (EV-GRS)
An alternative weight incorporates MAF as well as OR. The development of this score was motivated by the assumption that both MAF and OR are important factors to explain the genetic variance and heritability (Park et al., 2010). It has been developed to construct a weight in the risk modeling. The odds ratio estimates could be obtained identically as discussed above for the OR-GRS, and the MAF could be generated from NCBI and HapMap databases, or from the data at hand.
Simulation Design
Simulation design 1: interaction
In the current study, we simulated epistasis as multiple loci, non-additive disease risk models. In these simulations, the loci involved in the interaction model are independent (not correlated), but together interact to predict disease. This "statistical interaction" was simulated assuming that the multiple loci genotypes jointly contribute to an underlying (unobserved) continuous trait by varying their interaction term under a linear regression model. The disease occurs if this continuous trait exceeds a certain threshold.
Firstly, genotype Gi at SNP i was generated independently under Hardy-Weinberg Equilibrium (HWE). The genotype value was coded as 0, 1, and 2, representing the number of risk alleles. Minor allele frequencies (MAF) of the SNPs were set to 0.4 and 0.05, which resemble common and relatively rare variants. Continuous phenotypes Y were then generated conditional on genotypes, according to
where β0 = 20 and σ2 = 10. Binary affection status D was assigned to 1 (case) if phenotype Y > median(Y) and D was 0 (control) otherwise, where the threshold median(Y) was only chosen in order to achieve prevalence P(D) = 0.5 and balanced case and control data. Under this linear model, β = (β0, β1, β2, β3, β4, β34) was ranged to reflect different effect sizes (ES) among SNPs. SNPs 1 and 2 have main effects only, while SNPs 3 and 4 have interactions where β34 reflects the strength of interactions (Winham et al., 2012). In this simulation, main effect means SNPs contribute to the disease risk in an independent way only, while interaction effect defines SNPs are independent but attribute to the risk both marginally and dependently.
We considered 2 scenarios in simulation one, with 4 and 2 disease-causing SNPs respectively, with a total of 4 SNPs simulated. In scenario 1, our primary interest was to compare the performance of genetic risk models including only true "deleterious" SNPs. Four SNPs were causative with both main and interaction effects. In scenario 2, only SNPs 3 and 4 were causative with interaction effects. The priority was to investigate risk models when "noise" SNPs were present. In order to examine the effect of weight and interaction, important simulation factors involved MAF, effect size (ES) and interaction. All common variants, all rare variants, common plus rare variants were simulated with both same and different effect sizes among these SNPs, and three settings of interactions (negligible, moderate and strong) were considered, which led to 18 combinations in total. For each combination, 100 replicates were generated with 250 cases and 250 controls. In preliminary studies we simulated datasets with sample sizes of 1000. The results showed similar patterns and thus the additional details were not included.
Heritability in the broad sense is defined as the proportion of the phenotypic variance that could be attributed to variance of genotypic values, and in the narrow sense it is due to the additive genetic effect (Visscher et al., 2008). The specific heritability component mainly depends on MAF, ES and degree of interaction. Culverhouse et al. and Winham et al. have described the calculation of heritability in the presence of main effects and epistasis for binary traits as simulated here (Culverhouse et al., 2002; Winham et al., 2012). For a single locus A with genotypes a = 0, 1, 2, the heritability can be expressed as:
where P(Ga) is the genotype frequency of locus A, P(D) is the disease prevalence and P(D|Ga) is the penetrance. Penetrance was defined as the probability of disease conditional on a particular genotype combination at the disease risk locus/loci. Similarly, the total heritability due to the two loci A and B, with genotypes a, b = 0, 1, 2 respectively, is:
where P(Gab) is the frequency of genotype combinations of a and b, and P(D|Gab) is the corresponding penetrance. The heritability due to the marginal effect of locus A is defined as:
The heritability due to the interaction effect could therefore be interpreted as the proportion of that is not attributable to the marginal effects by either locus, that is:
This heritability calculation method could be generalized to a scenario with more causal SNPs. The property of our simulated models could be reflected by varying heritability component due to the main effects (H2G1G2 = H2M, G1 + H2M, G2) and interaction effects (H2G3G4 = H2M, G3 + H2M, G4 + H2I, G3G4). Low heritability (H2Total = H2G1G2 + H2G3G4 < 5%) was chosen to reflect detectable effect sizes in the realistic genetic association studies and to ensure the reasonable power to discriminate the difference of performance (Winham et al., 2012).
Supplemental Table S1 summarized the simulated model specifications in terms of MAF, ES, interaction and heritability.
Simulation design 2: linkage disequilibrium
In simulation two, SNP linkage disequilibrium (correlation) was investigated. We assumed two loci were correlated regardless of disease outcome. To mimic linkage disequilibrium, simulations were performed by designing the genotype combination frequencies of two or more loci, and in turn contributing to disease in an additive but relatively independent fashion under a probabilistic model. We simulated a true disease risk model involving two independent "deleterious" SNPs (SNPs 1 and 2). Two scenarios were considered with SNP 3 was dependent (strong LD model) and independent (weak LD model) of SNP 2 respectively. SNPs 1 and 2 were generated as multinomial under HWE, and then SNP 3 was generated according to Supplemental Table S4. In Scenario 1, for each level of SNP 2 values, the genotype frequencies of SNP 3 varied. We defined that SNPs 2 and 3 were in strong LD (correlated). In Scenario 2, the genotype frequencies of SNP 3 were fixed and irrelevant to the genotype of SNP 2. In this case, we defined SNPs 2 and 3 were in weak/no LD (non-correlated). GRS approaches were compared when only "deleterious" SNPs were included (true model), or when all three SNPs were included (Scenario 1 strong LD: true + dependence model; Scenario 2 weak LD: true + independence model). In the case of weak/no LD, including the third SNP could also be thought of as including a false positive locus.
Rather than the linear model in simulation one, a direct probabilistic model was used here to generate the disease status. To simplify, an additive genetic mode was determined. Let the alleles from SNP 1 be denoted "A" and "a", and let those from SNP 2 be denoted "B" and "b". Then, SNP 1 has three genotypes as "AA", "Aa" and "aa", whereas SNP 2 has three genotypes as "BB", "Bb" and "bb" correspondingly, thus leading to nine genotypes combinations. Table 1 demonstrated the penetrance pattern for two-locus main effect model for nine genotypes combinations, where k was the baseline penetrance and θ was the specified relative risk (RR) of having a disease between different genotypes for each SNP.
As presented in Supplemental Table S5, MAFs ranged from 0.4 to 0.05 to represent common and relatively rare variants. Four scenarios were included, one where both SNPs 1 and 2 were common or rare, one where SNP 1 was common and SNP 2 was rare, and vice versa. Relative risks (RRs) considered in our model were either 1.25 or 1.75 to simulate different effect sizes between SNPs 1 and 2, and 1.5 to simulate models where both SNPs had the same effect sizes. Baseline penetrance k was fixed at 0.1. Balanced (equal allocation) case-control data was simulated with a total sample size of 400. 100 replicates were simulated as training data to calculate external weights for OR- and EV-GRS approaches, and then another 100 replicates were generated as test data to evaluate the performance of GRS methods.
Data Analysis
The main focus of the prediction modeling was to determine the true risk model correctly. In general, the training data sets were used to derive weights for the weighted GRS methods, assuming all causative SNPs are known. For each method, the GRS were calculated for each subject in the test data. A logistic regression model was applied to fit the test data using each genetic risk modeling approach respectively, with a summary GRS as the only predictor. We used power, type I error, C-statistic and Akaike information criterion (AIC) to evaluate the performance of each of the GRS. Power or type I error rate was calculated as the number of times the model is statistically significant at P-value <0.05 across the number of simulated replicates (Che et al., 2012). A likelihood ratio test was used as the global measure of model fit. In the simulation study, if the binary case/control status was assigned based on the specific genetic values, the detection ability could be reflected by power. In contrast, if the case/control status was irrelevant to genetic variants, the type I error under the null simulation then could be interpreted as false positive rate. The best risk score approach was expected to detect the model if it is true, whereas to control the probability to incorrectly accepting the false model. The C-statistic measures the discriminatory capability of each model to distinguish case from control. AIC is a measure of the goodness of fit of the model, which describes the tradeoff between accuracy and complexity of the model (Che et al., 2012). In general, a model is preferred if it has larger power and C-statistic and has a smaller AIC, with a reasonable type I error.
Under the null model (involving only "noise" SNP), the P-value for the likelihood ratio test was recorded for each replicate, and then the number of times across the 100 replicates that the P-value was less than 0.05 was calculated as the type I error. Under the true disease risk model (involving any causative SNP), the C-statistic, AIC and P-value for the likelihood ratio test were recorded. The power was calculated as the proportion of times a true model was correctly identified (P-value < 0.05) across 100 replicates. For each model, the C-statistic and AIC were averaged across all replicates. All results were statistically evaluated for differences under a generalized linear model, and Tukey's method was used to adjust for pair-wise contrasts between methods, which has been described previously (Winham et al., 2010; Che and Motsinger-Reif, 2012).
In simulation one, data generation was performed on R platform (www.r-project.org). For all the remaining data simulations and analyses were applied using SAS 9.2 (www.sas.com).
Simulation Result 1: Interaction
In Scenario 1, with four deleterious SNPs, both main and interaction effects exist. Figure 1i shows the power results when all the SNPs have similar effect sizes. If there is no interaction between SNPs 3 and 4, the weighted and unweighted methods are equivalent. When all SNPs are common variants (Figure 1A) or both common and rare variants (Figure 1C), as the degree of interaction increases, the weighted methods outperform the simple count GRS. However, when all SNPs are rare variants, the power of three methods is identical.
Figure 1. Power comparison for the interaction model with four deleterious SNPs. Panels by column: (A) All SNPs are common variants. (B) All SNPs are rare variants. (C) SNPs 1 and 3 are common variants, and SNPs 2 and 4 are rare variants. Panels by row: (i) SNPs have same effect size. (j) SNPs have different effect size.
In Figure 1j, when the effect sizes among SNPs vary, it is clear that the weighted methods are consistently preferable to the unweighted one. There is no significant difference between the two weighted methods, OR- and EV-GRS.
In Scenario 2, the total heritability is due to SNPs 3 and 4 only, and then SNPs 1 and 2 were simulated as "noise" SNPs. As expected, the weighted methods show improved power over the simple count method across all models (Figure 2).
Figure 2. Power comparison for the interaction model with two deleterious SNPs. Panels by column: (A) All SNPs are common variants. (B) All SNPs are rare variants. (C) SNPs 1 and 3 are common variants, and SNPs 2 and 4 are rare variants. Panels by row: (i) SNPs have same effect size. (j) SNPs have different effect size.
Simulation Result 2: Linkage Disequilibrium
Scenario 1 shows the strong linkage disequilibrium model when SNPs 2 and 3 are correlated. As demonstrated in Figure 3i, all three methods have similar power if only deleterious SNPs with similar effect sizes are included in the risk model (true model). However, if the dependent but non-causative SNP 3 is added (so a model including true loci plus marker(s) that are correlated with the true loci), the power of SC-GRS declines rapidly.
Figure 3. Power comparison for the strong linkage disequilibrium model when SNPs 2 and 3 are dependent. Panels by column: (A) SNPs 1 and 2 are common variants. (B) SNPs 1 and 2 are rare variants. (C) SNP 1 is common variant, and SNP 2 is rare variant. (D) SNP 1 is rare variant, and SNP 2 is common variant. Panels by row: (i) SNPs have same effect size. (j) SNPs have different effect size. "Dep" means SNPs 2 and 3 are dependent.
For the scenarios where there are different effect sizes of the causative SNPs (Figure 3j), the results of the power comparison are very similar, except the weighted methods are also preferable when the causal variants are common (Figure 3Aj).
A similar pattern is observed when SNP 3 is independent and non-causative in the weak linkage disequilibrium model, as shown in Figure 4.
Figure 4. Power comparison for the weak linkage disequilibrium model when SNPs 2 and 3 are independent. Panels by column: (A) SNPs 1 and 2 are common variants. (B) SNPs 1 and 2 are rare variants. (C) SNP 1 is common variant, and SNP 2 is rare variant. (D) SNP 1 is rare variant, and SNP 2 is common variant. Panels by row: (i) SNPs have same effect size. (j) SNPs have different effect size. "Indep" means SNPs 2 and 3 are independent.
In summary, the weighted approaches outperform the SC-GRS across all scenarios in terms of power and C-statistic (P-value <0.05), as shown in Supplemental Tables S6, S7. EV- is slightly better than OR-GRS, with no significant difference. In respect to AIC, there is no significant difference.
For the null simulations, the type I error rates across all models are well reasonably controlled (data was shown in Supplemental Tables S3, S5). There are no statistically significant differences in terms of type I error among these methods and the cut-off value 0.05. While SC-GRS has the lowest type I error, EV- is still preferable than OR-GRS (Supplemental Table S6).
Table 2 summarizes the results of significance tests of the pairwise contrasts of the different methods. For each table cell, if one method significantly outperforms the other, that method is listed. As these results show the weighted methods perform better than the SC-GRS in terms of power and C-statistic, but there is no significant difference between OR- and EV-GRS for these measures of performance.
Table 2. Significant winner* in pair-wise method comparisons in terms of power, type I error, C-statistic and AIC.
The primary goal of our study was to explore how interaction and correlation could impact the risk prediction and to further determine the usefulness of genetic risk score as a predictive model that allows for gene-gene interaction, assuming sample sizes and genetic effect sizes likely to be encountered in real genetic studies. Since in real data the underlying disease mechanism is often unknown and is likely to vary across diseases, we try to employ relatively comprehensive simulation strategies to resemble potential complicated sources of interaction. Based on a wide range of simulation experiments, we observed that the weighted methods generally outperform the simple count method.
In simulation one, as expected, we observed a clear and intuitive relationship among effect size, MAF, heritability and power for all methods. For instance, in the case of MAF3 = MAF4 = 0.4 and ES3 = 0.2, H2G3G4 increases from 0.2 to 0.9% when ES4 increases from 0.2 to 0.5 (models 1–4). In the case of MAF3 = MAF4 = 0.05 and ES4 = 0.8, H2G3G4 increases from 0.4 to 0.7% when ES3 increases from 0.2 to 0.8 (models 10–7). The increase of heritability is more rapid for common variants. In respect to the MAF and heritability, in the case of ES3 = ES4 = 0.5 and MAF3 = 0.4, H2G3G4 increases from 0.9 to 1.5% when MAF4 increases from 0.05 to 0.4 (models 31–19). In the case of ES3 = 0.2, ES4 = 0.8 and MAF4 = 0.05, H2G3G4 increases from 0.4 to 0.5% when MAF3 increases from 0.05 to 0.4 (models 10–16). It is consistent with the assumption that both effect size and MAF are essential to drive the heritability and the impact of effect size seems more obvious. We also observed a clear pattern of heritability and power. The power of SC-GRS has improved from 26 to 75 and that of weighted GRS from 26 to 85, as the total heritability increases from 0.5 to 1.7% (models 1–4). Therefore, it becomes easy to identify the risk model when the heritability is high.
To further demonstrate the relationship between the potential important factors and heritability, we utilized two-locus model to calculate the heritability due to total, marginal and interaction, according to formulas 13–15 respectively. Figure 5 portrays a clear relationship between effect size, minor allele frequency, risk allele frequency, interaction effect and heritability. Firstly, we assumed there is no interaction between two loci (panels A–C). Similarly, common variants have MAF = 0.4 and rare variants have MAF = 0.05. In panel (A), ES1 was fixed at 0.1 if two loci were common, whereas ES1 was 0.3 if two loci were rare. When ES2 increases from 0 to 0.5, the total heritability and marginal heritability due to SNP 2 increase more rapidly for common than rare variants. In panels (B–C), effect sizes for two loci were fixed at 0.5 and SNP 1 was considered as common and rare respectively. The total and marginal heritability due to SNP 2 increase as MAF2 increases from 0 to 0.5, and decline as risk allele frequency (RAF) 2 increases from 0.5 to 1. This relationship pattern further illustrates the validity of explained variance genetic risk score. Both the log scale of effect size and the square root of minor allele frequency are appropriate to explain the genetic variance due to SNP (that is heritability), and thus it is reasonable to incorporate both ES and MAF to construct the weight. Secondly, we investigated the relationship between interaction effect and heritability, and the results were shown in panels (D–F). Both marginal effect sizes were set to 0.1 for panel (D) (common variants) and 0.4 for panel (E) (rare variants). In panel (F), SNP 1 was common and SNP 2 was rare, but they were set as the same effect size 0.2. We considered both positive (β12 > 0) and negative interaction effect (β12 < 0). For positive interaction, when interaction effect increases, the total, marginal and interaction heritability increase consistently (panels D–F). Furthermore, as the interaction effect increases, the marginal heritability due to rare variant is more sensitive than that due to common variant (panel F). However, it is relatively complicated to account for negative interaction effect. The pattern depends on both marginal and interaction effect sizes. It also explains the complicated pattern for Figures 1, 2. As the negative interaction effect increases, the heritability may either increase or decrease, which in turn affects the power. Therefore, this relationship pattern provides some theoretical evidences for the weight construction method of EV-GRS, as well as the complicated pattern of the risk score model performance.
Figure 5. Relationship between effect size, minor allele frequency, risk allele frequency, interaction effect and heritability. (A) Relationship between heritability and effect size. (B) Relationship between heritability and minor allele frequency. (C) Relationship between heritability and risk allele frequency. (D) Relationship between heritability and interaction effect when SNPs are common variants. (E) Relationship between heritability and interaction effect when SNPs are rare variants. (F) Relationship between heritability and interaction effect when SNPs are common and rare variants.
To further address the role of allele frequency in the heritability, we applied one-locus model to calculate the heritability (formula 12). Effect size was fixed at 0.5 and risk allele frequency ranged from 0 to 1. Explained variance weight was obtained using formula 8, where the effect size was equivalent to log odds ratio in the logistic regression model. In Figure 6A, we observed a clear positive correlation between heritability and EV weight, which emphasized the role of allele frequency besides effect size. As to the relationship between heritability, EV weight and RAF, Figures 6B,C shared a similar pattern.
Figure 6. Relationship between risk allele frequency, explained variance weight and heritability. (A) Relationship between heritability and explained variance weight. (B) Relationship between heritability and risk allele frequency. (C) Relationship between explained variance weight and risk allele frequency.
It should be noted that the performance of all three GRS models do not significantly differ for the models with rare variants with the same effect sizes, regardless of the strength or presence of interaction (Figure 1Bi). Referring of the total heritability of these models, it is understandable that the heritability due to interaction between SNPs 3 and 4 is very low, ranging from 0, 0.1 to 0.2%, while the total heritability is around 1.5% (models 7–9). This demonstrates the concept that the heritability due to only rare variants is limited, and thus GRS modeling may not work effectively in prediction with all the rare variants. Furthermore, in the scenario of all rare variants with similar effect sizes, weighted and unweighted methods are identical even if the interaction exists. Nevertheless, weighted methods are still preferable if different effect sizes exist, in all cases of MAF.
Understanding that current simulations may include a limited number of SNPs and low level interaction, as a follow up we also considered more complicated scenarios with six disease-causing SNPs. As shown in Supplemental Table S2, model 37 involved two two-way interactions, by varying the interaction term of SNPs 3 and 4 (β34) and that of SNPs 5 and 6 (β56). Similarly, model 38 involved three-way interactions, where SNPs 3, 4, and 5 were interacted to cause disease by specifying β345. The power improvement of the weighted GRS approaches were exaggerated compared with the SC-GRS. The details of results were presented in Supplemental Table S3. It seems that the impact of simulated effects may be amplified by the number of SNPs and the degree of interaction. Based on our empirical evidences, we expect these results could be generalized to larger models, but the extrapolations should be interpreted cautiously. Future studies should further evaluate the performance of these GRS methods for larger, and increasingly complex models.
In general, weighted and unweighted approaches are equivalent only if the true model is fully discovered, all causative SNPs have identical effect sizes and no interaction exists. However, it is almost impossible to satisfy all three requirements in practice. As the strength of interaction increases, the power of SC-GRS declines rapidly, while the advantage of weighted approaches becomes more obvious. If there are "noise" SNPs involving in the risk score, the weighted methods could limit the negative influence of the non-causative SNP. The performance of weighted method does not diminish when non-causative SNPs are added, and whether it is in strong or weak LD with true SNP. It is intuitive the performance of the weighted methods are greatly improved if the effect sizes of causative SNPs vary. As to the comparison of the weighted GRS approaches, EV- is preferred than OR-GRS with stronger power and lower type I error over these scenarios, but the difference is not statistically significant. Although it is believed that MAF is an important factor to explain the genetic variance and heritability, the effect size may still dominate the overall direction of the weight (Park et al., 2010). More comprehensive studies of MAF in the presence of interaction may be necessary.
In summary, our findings allow us to draw a consistent conclusion that weighted genetic risk score models are superior to the unweighted one overall and EV-GRS is the most robust approach, in the presence of potential genetic interactions, LD and false positive predictors. It provides some useful guidance for researchers in selecting an appropriate genetic risk score and advocates a wide implementation of the robust EV-GRS in real data analyses. It should be noted that beyond the discovery and identification of novel genetic variants, we are more focused on the follow-up direction to utilize these identified variants to predict the disease risk or the effectiveness and toxicity of interventions in pharmacogenetics study. Although the application of risk prediction in the complex disease has been limited due to complexity, several interesting evidences support application of prediction model in pharmacogenetic study is appealing and encouraging (Hess et al., 2006; Klein et al., 2009; Ritchie, 2012). Also, we are interested in the sensitiveness and robustness of the risk model. We should be cautious to use over-optimistic estimates for the risk factors, particularly in pharmacogenomics studies (Ritchie, 2012). In this sense, weighted methods perform robustly overall. Notably, it is reasonable and straightforward to assign more weights to important factors and limit the weights for seemingly noisy predictors.
Despite these solid conclusions, we recognized our study does not explicitly simulate more complex architectures and thus some inherent limitations remain to address. We only considered simple disease models involving marginal effects and two-locus interactions. Also, a limited number of scenarios of LD were examined. In future studies, it would be of great interest if we expand simulations to high-order gene-gene interactions, or even involving gene-environment interactions. Although it was not a thorough list of all complicated scenarios, our findings still provide insight that weighted risk model may play an vital role in the risk prediction when interaction or LD exists. Furthermore, current GRS models assume an additive model and independence of SNPs, which would rarely be the case. Despite the advantages of weighted GRS under the violation of these assumptions, the innovation of GRS that incorporates interaction term(s) will definitely be an important future direction. It is believed that to account for interaction or more complex architectures appropriately, the refinement and extension of risk models becomes an important priority in the human genetics.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary Material
The Supplementary Material for this article can be found online at: http://www.frontiersin.org/Statistical_Genetics
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Keywords: explained variance, genetic risk score (GRS), interaction, linkage disequilibrium (LD), predictive modeling
Citation: Che R and Motsinger-Reif AA (2013) Evaluation of genetic risk score models in the presence of interaction and linkage disequilibrium. Front. Genet. 4:138. doi: 10.3389/fgene.2013.00138
Received: 30 December 2012; Accepted: 01 July 2013;
Published online: 23 July 2013.
Edited by:Joanna Biernacka, Mayo Clinic, USA
Reviewed by:Marylyn D. Ritchie, The Pennsylvania State University, USA
William S. Bush, Vanderbilt University Medical Center, USA
Copyright © 2013 Che and Motsinger-Reif. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Alison A. Motsinger-Reif, Department of Statistics, Bioinformatics Research Center, North Carolina State University, 307 Ricks Hall, 1 Lampe Dr, Raleigh, NC 27695-7566, USA e-mail: email@example.com


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Zenwatch 2
The Asus ZenWatch turned some heads when it was released in 2014, but with more of the market moving towards round faces, nobody knew what to expect for its successor. The Asus ZenWatch 2 was announced at IFA in 2015 and released in September of 2015. The ZenWatch 2 was different from its predecessor due to the fact that it was offered in two different sizes; 49mm and 45mm with strap sizes of 22mm and 18mm, respectively.
Smart Outdoor Watch
Casio is a name familiar to the watch industry. The Smart Outdoor Watch marks the legendary company's first foray into smartwatches. The watch was announced at CES 2016 and marketed to fans looking to live an active lifestyle.
While it isn't the cheapest watch out there, you do get many features not included in most Android Wear smartwatches. A rugged design, water resistance, and many connected apps, just to name a few.
Huawei Watch
The Huawei Watch isn't Huawei's first foray into the smartwatch world, but, it was its first smartwatch to feature Android Wear. The Huawei Watch was announced at Mobile World Congress in February of 2015 and officially released in September of 2015.
Huawei has impressed so many with its first smartwatch that some say its the best on the market. The Huawei Watch is a beautiful Android Wear device and is definitely worth checking out.
Huawei Watch for Women
Q Founder
2015 brought several new traditional watchmakers to the Android Wear community, one of the most notable being Fossil. The legendary watchmaker released a few watches, most notably the Q Founder.
The Q Founder sits in the same price range as watches like the Moto 360 while offering stunning looks and great reliability. It hasn't caught on with fans as much as Fossil might like, but we may see that change in later half 2016 as the watch continues to gain popularity. In a crowded market, Fossil is looking to give customers a reason to choose them over the rest of the field.
Watch Urbane
The predecessor to the LG Watch Urbane 2nd Edition, the LG Watch Urbane put LG on the forefront for beautifully designed Android Wear smartwatches. Previously, LG had released the LG G Watch, and the LG G Watch R, but neither really had that full-on "professional" look going for them. The LG Watch Urbane changed that and shook the market up a bit.
Announced in February of 2015, and released in April of 2015, the LG Watch Urbane has been the trendsetter leading up the professional-looking Android Wear smartwatches that we have seen released at the end of 2015. The LG Watch Urbane took a little bit of a popularity hit due to its price tag, but considering that LG was using the Urbane to compete with the Apple Watch, the popularity hit went back up among those Android faithfuls.
Watch Urbane Second Edition LTE
Moto 360 First Edition
Arguably the most beautiful Android Wear device to hit the market, the Moto 360 was announced in March of 2014, and after months of speculation was released to the world in September of 2014. The Moto 360 was the one of the first Android Wear devices to be released, alongside the LG G Watch and Samsung Gear Live, and held the claim of being the most beautiful Android wear device of 2014 and into 2015.
The Moto 360 was teased over and over again by Motorola, and there even was an event where journalists were allowed to play around with it before the spec list was released. The Moto 360 set the precedent for beautifully designed Android Wear devices, and although its successor has been announced, it's still the device to beat aesthetically.
Moto 360 Second Edition
Arguably the most beautiful Android Wear device was released in late 2014, the Moto 360. Folks everywhere were wondering how Motorola was going to follow up the great first run with an Android Wear smartwatch, and whether that annoying flat-tire would still be around. When the new Moto 360 started getting leaked, people were disappointed, until they saw it in person.
The 2015 Moto 360 still has that flat tire that houses the various sensors, but Motorola was quick to let everyone know that the display to bezel ratio was better than any smartwatch available today.
Moto 360 For Women
Moto 360 Sport
The Moto 360 Sport kind of came out of left field, as no one was really expecting Motorola to release a sporty rendition of its Android Wear devices. While the Moto 360 sport has a round face, similarly placed crown/button, and the flat-tire that is found on the Moto 360, that's where the similarities end. The Moto 360 Sport is clearly designed for those who want to have a great looking smartwatch, even while working out.
On top of the pretty unique and awesome design, the Moto 360 Sport combines fashion with function due to the built-in GPS with compatibility with running apps such as Endomondo, Run Keeper, and others. The Moto 360 also allows you to measure your lifestyle activities, steps, calories burned, and more. The Moto 360 Sport isn't your traditional Android Wear smartwatch, but then again, there aren't many things that are traditional when it comes to Motorola.
Smartwatch 3
The Sony SmartWatch 3 is the third rendition of smartwatches released by Sony, but the first that features Android Wear. The first two renditions featured Sony's own proprietary software but was removed with the SmartWatch 3. Announced at IFA 2014, and released in November, the SmartWatch 3 was the first Android Wear device to feature GPS built-in.
The added GPS was due to the fact that the SmartWatch 3 was seemingly geared towards runners and those workout fiends. Then, after the initial launch, Sony added a Stainless Steel option to the lineup, for those who liked the SmartWatch 3, but wanted a more professional look and feel. Sony has yet to release a new version, but it should only be a matter of time before something new is announced from the Japanese tech giant.


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IN a gesture of goodwill towards the USA, North Korean dictator Kim Jong-un released three American prisoners from a brutal labour camp.
Donald Trump was delighted with the move from the secretive nation. Here is everything we know about them.
Who are the freed North Korean prisoners Tony Kim, Kim Hak-song, and Kim Dong-chul?
The three American citizens were languishing in a brutal North Korean labour camp for almost a year before they were released by dictator Kim Jong-un as a goodwill gesture.
Tony Kim, Kim Hak-song and Kim Dong-chul were jailed for more than a year in gulags but said to be in good health. Here is what they were being held for:
- Kim Hak-song was held by the secretive nation on suspicion of "hostile acts" in May 2017. He had described himself as a Christian missionary who planned to start an experimental farm at the Pyongyang University of Science and Technology. Kim was born in Jilin, China, and educated in California after moving to the US. He was also an ordained evangelic Christian pastor.
- Tony Kim also known as Kim Sang-duk, also worked at the university and taught accounting. In April 2017 he was detained on espionage charges. South Korean media reported that he had been involved in humanitarian work in the North.
- Kim Dong-chul is a pastor in his early 60s and was arrested in 2015 on spying charges and later sentenced to 10 years hard labour in April 2016. He was born in South Korea and spent the longest time in the gulag. Before his sentencing the former Virginia resident publicly apologised for slandering North Korea's leadership, collecting and passing confidential information to South Korea, and joining a smear campaign against the North's human rights situation.
It is not known if Kimg Hak-song and Tony Kim were ever formally convicted sentenced for their alleged crimes against the secretive state.
The last American prisoner to be freed by the dictator, Otto Warmbier, was returned to the US in a vegetative state 15 months after his conviction of crimes against the state and later died.
Has Donald Trump met them?
The US president announced on Twitter that he would be greeting the freed prisoners when they touched down on American soil.
The tweet reads: "Secretary Pompeo and his "guests" will be landing at Andrews Air Force Base at 2:00 A.M. in the morning. I will be there to greet them. Very exciting!"
The former detainees touched down at a US Amry base in Maryland in the early hours of May 10 and were greeted by a beaming President Trump, who boarded the plane to shake their hands as they exited the aircraft.
The trio made peace signs and smiled as they finally returned to American soil after a lengthy flight home via Japan.
Trump's wife Melania was also there to welcome the former prisoners back home.
What have their families said about their release?
While Tony Kim and the two other American citizens were detained his son Sol Kim released a statement praising those who were making efforts to free his father.
His statement reads: "'My family and I appreciate the ongoing support for the release of the 3 Americans (#USA3) detained in North Korea including my dad, Tony Kim. We are hopeful but we have no indication that they have been released. Thank you for your continued prayers and efforts to help bring them home. We look forward to all of the families being reunited very soon.' – Sol Kim"
His family have also been vocal since Tony Kim's release was secured by the North Korean dictator's goodwill gesture.
Their statement reads: "We are very grateful for the release of our husband and father, Tony Kim, and the two other American Detainees. We want to thank all of those who have worked towards and contributed to his return home. We also want to thank the President for engaging directly with North Korea. Mostly, we thank God for Tony's safe return.
"We appreciate all of the support and prayers of friends and even strangers during this challenging year. You are dear to our hearts.
"We ask that you continue to pray for the people of North Korea and for the release of all those who are still being held."
Tony Kim will be able to meet his grandchild for the first time now he safely back on US soil.
FESTIVAL SEASON'Naked News' TV reporter Jenny Scordamaglia parties at Spanish festival in her latest outrageous stunt
In an interview with CNN before the prisoners release was secured Kim Hak-Song's wife said: "I believe 100 per cent that you served our people with love.
"I hope you can stay strong there and hope that you can return to our family very soon."
She found out her husband had been detained in North Korea after he didn't return home from a business trip from the secretive state.
She added: "I waited until the last passenger left the train. The train doors closed, but he didn't come out."
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acoucité is partner of the European research project Monica. This project is part of a progress approach for a smart and sustainable city through the use of IoT-enabled devices. Funded by Europe, it gathers 28 partners from 6 urban areas … Continue reading
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1 June 2016
Harmonica project awarded by the European Commission
Bruifparif received last evening at Bruxelles, during the EU Green Week 2016, one of the 24 Best Life Environment Projects awards for the Harmonica project lead from 2011 to 2015 in partnership with acoucité. The project was selected by the … Continue reading


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A writer grappling with his characters
– or is it the other way around? –
in an impish homage to Jean-Luc Godard
and Anna Karina.
Followed by 'A tale without a name',
a layered short story plugged into
Four of these outstanding Thai short stories
are published in English for the first time.
The others appeared first in the Bangkok Post.
All mark new trends in Thai fiction writing
and deserve the widest readership....
the doll
an old cloth and a tray of mackerels
the last drop of ink
Alongside Rart Eikkatheit's Three Worlds, four more samples of the work of the most imaginative and versatile Thai writer of experimental...
Bangkok in the late 70s.
A tenanted house between jungle and modern civilisation.
The girl next door is struck down by cancer and goes for Thai cures.
Alternately self-righteous, smug, kindly and selfish,
20 loans
20 at a time
Thirteen short stories spanning a quarter century
by the most incisive Thai satirist of the times
A variety of styles and moods by seven leading Thai short story writers of today:
A traffic-wise couple – Sila Komchai
Blood buds – Sila Komchai
The lookers-on – Korn Siriwatthano
A bamboo bridge over rapids...
Soldier, pimp or artist?
What is Rart's real nature?
Is history repeating itself?
By the most inventive and versatile of Thai short story writers,
a tale of social upheavals and human ambiguities
that can...
20 loans
20 at a time
A 1930s Thai romance with a Japanese setting
and a political message
by one of the best stylists of Siam
20 loans
20 at a time
A crippled boy plays with his puppets and dreams of glory
until the female cobra he disturbs by his show rushes at him.
The life-and-death struggle that follows has but a predictable end
– or has it?
20 loans
20 at a time


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A Very Vintage Christmas
One of the most highly anticipated fairs of the year opened its doors yesterday for their annual Christmas Fair at the Business Design Centre in Islington. The Country Living Magazine Fair hand-picks some of the best artisans, crafters, designers, antique and vintage sellers to participate in their fabulous five day fair. Not only can you shop to your heart's content but you can also visit the Lifestyle Theatre for a selection of demonstrations and talks ranging from simple gift wrapping, making flavoured chocolate to florals for Christmas just to name a few. And on Friday 1st November, Kirstie Allsopp will be running a Christmas Craft demo and then a book signing at 11.30 (until 12.00). This year there are around 40 new stallholders who join nearly 300 seasoned sellers and the choice for vintage or antique gifts is wonderful.
Chloe Antiques (Stand J33) offers handmade gifts using exquisite antique textiles. I always admire her Christmas fairies which would look fabulous on any tree, not to mention a wonderful heirloom to pass down.
Chloe makes beautifully scented lavender bags, embroidered hearts and tiny Christmas tree stockings and any fabric remnants left over are made into fabric and trimming packs to sell, which are always snapped up. Her bunnies are also a popular buy.
Everything is beautifully displayed – even this gorgeous Armoire (below) was for sale. I adored the felted dogs.
And talking of dogs, Daisy's Dog Deli (Stand P69a) offer wholesome dog treats, hand baked with fresh ingredients that looked good enough to eat!! I loved that you can order a Santa Paws Hamper which can be delivered direct to your dog – I am sure our dog would scoff it in one!
I raced around to find Rosie's Armoire (Stand J44) where Helen always manages to find the most amazing vintage ephemera – I thought these vintage numbers would look great on a special 13th, 18th and 21st birthday present.
Bundles of 'vintage inspiration' are for sale and other little vintage gems.
She also hand makes some exclusive items likes these handbags and vintage velvet pin cushions or hatpin holders – one of which sits proudly on my sewing table.
Caroline Zoob (Stand D1) always has people beating a path to her stand and the queues for her selection of handmade, vintage and vintage like items are legendary.
I was very drawn to these charming small lavender pillows which are created by Emily Maude (Stand J47) who loves to illustrate and is inspired by recapturing periods in history.
These are her charming notebooks.
And the bird theme carries over into bird garlands, ornaments and greeting cards.
I absolutely loved these hand crafted cakes and biscuits by Sucre Coeur (Stand F28). Husband and wife team McCormack and McCormack lavishly decorate these traditional fruitcakes and gingerbread cookies. Dave does the baking, Karen does the decorating and Dave washes up – what a perfect arrangement!!
They will happily post any of their delicious festive goodies and have even shipped to New Zealand. I can also vouch for the macarons which are teeny tiny ones beautifully displayed in a long box which I had every intention of photographing when I got home but cough cough they didn't last long enough – my husband and son devoured them.
These patterned paint rollers have been the talk of the interior world and these lovely designs from The Painted House (Stand J2a) are no exception. Clare spotted these designs in Romania where they have been used for many years as an alternative to wallpaper. There are 18 designs to choose from and you can also use the rollers on fabric. Customers have also used them to upcycle chest of drawers and other interior wood items to great effect.
Other very worthwhile stands to visit are my favourite Garden Brocante (Stand G7) for a great collection of vintage jewellery, vintage cutlery, silver and homewares; Calon Company (Stand D22) who bring gorgeous vintage blankets from Wales along with handmade items, haberdashery, bedding and vintage china. I got a lovely sewing pattern – I have no intention of ever sewing (as it would be too difficult for me) but the picture on the front was so lovely I just had to have it.
Ludvig Design (P35a) makes the most gorgeous handcrafted jewellery with silver, gold, stones, pearls and crystals. Some of the designs are very fine and delicate which I fell in love with as they looked very dainty on and everyone was oohing and aahing over them; and of course Jane Means (Stand A8) for her great range of ribbons and decorations – Jane is the gift wrap guru of the UK who offers courses and instructional DVD's as well.
I've only told you about a very small number of stalls that caught my eye but there is something for everyone at the fair including of course the popular food hall with lots of 'tasters' and Christmas goodies. No need to watch that waistline!
The fair is at the Business Design Centre, 52 Upper Street, Islington, London, N1 0QH.
The website has all the necessary information on opening times, programmes and floor plans.
You'll cross off that Christmas List in no time!


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I have to admit that short stories about Succubi and Incubi are the rule and not the exception. I understand that and I try to keep that in mind when I read such works. The problem becomes when the story isn't done well or just leaves the story for the sex instead.
I like story with the heat. And having sex without really explaining why and who and how it comes to be? That bothers me a lot… More than I like to admit actually…
- Title: The Witch and the Incubus
- Author: Ally Mauser
- Publishing Date: August 25, 2011
- Length: Novella (7 Pages)
- This work in Kindle format at Amazon.com
- This work at Smashwords.com
The story is about:
A powerful, ancient, and beautiful witch knows it is time to harvest the incubus boy's sexual energy. It should be a routine seduction, but something unexpected happens.
This is a very, very short story. The characters are barely fleshed out, the reasons for what happens are so thinly explained that for the most part they aren't.
It bothers me that all of the characters feel like cardboard cutouts. They are so flimsy in their actions that it makes the entire work feel like the author had an idea for a story and wrote a short summary of it, then published that instead of the actual story.
The work needs an editor. There are several words that are placed in the story that do not belong there. For example the word "mike" is used in one sentence that should have used "milk" instead. There are also a number of tense problems in the story that were jarring as well.
The surprise in the story, when it appears, is not exactly well done at least to me. Not going to reveal it here, but honestly I think that the resolution of the work could have been written better, explained more, and made me actually care about what happens to each of the characters.
The incubus in the story is young. The witch believes that he is seventeen at first, but that isn't right and his true age is eighteen which, for me personally, made the story a little easier to read. While some oblique references are made to his powers and physical attributes, there isn't much else that we learn about him. The information, when it is given, is in a sort of scattergun approach of little bits of information and then we move directly from that to what the witch is thinking and trying to accomplish.
But then this isn't meant to be a long story or something that is more than a stroke story for the most part.
The sex scenes were for me superficial. Not that hot and not that interesting to me personally, but then I don't particularly like the kind of sex that was prevalent in this work. That's my personal issue and I am sure that there are people out their that will disagree with me…
But that's a manner of opinion and this is all mine isn't it?
I'll give this work one out of five pitchforks.
Too short, too rushed, was not honestly that interesting to me to read… But then it was a short read wasn't it?


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To Voters,
Ballots will be coming to your mailboxes this coming week, and they will be crammed full of ballot issues for you to decide upon, as well as state-level candidate races. Make sure to check out the Blue Book and read up on them. There could be consequences – including unintended ones – whichever way you vote on each issue, proposition, initiative or race.
– Col. Morgan
To Fort Morgan City Council,
Good call on holding a meeting just to go over the history of your goal for consolidating city facilities and replacing old buildings that no longer meet the city's needs. It worked out well, with resident getting to express their feelings and offer you some direction and new ideas of their own.
– Col. Morgan
To Brush City Council,
The proposed lamb harvesting facility could bring a good batch of primary jobs to your community, and it is a good step toward re-purposing the old feedlot property. However, I am curious about whether your community has the housing to support an additional 50 workers and their families who will be needed within a year or less.
– Col. Morgan
To Farmers,
With the U.S. Department of Agriculture declaring a natural disaster area in Morgan County related to the July 29 storm, there could be more relief available to you. If you had flattened crops, ruined buildings or killed livestock related to that storm and haven't done so already, contact the Farm Service Agency to find out what help may be out there.
– Col. Morgan
To Fellow Downtown Fort Morgan Denizens,
See what you get for complaining in Fort Morgan? After last week's suggestion to rid the downtown of the dentist's office music filling the streets, whomever is the city DJ capitulated and changed it to…wait for it…opera. Yes, opera. I'll never complain again about the music for fear the next choice will be gospel rap.
– Col. Morgan
To Williams Family Foundation,
I was heartened to hear about your creation of an endowed chair for the director of the bachelor's of science in nursing program at Morgan Community College. Once it gets going, your contribution will help make the program sustainable.
– Col. Morgan
To St. Jude's Auction Bidders, Buyers,
A tip of the cavalry cap. You helped make it a good auction that raised money for a great cause.
– Col. Morgan
To Brush VFW,
Your Hall of Honor looks like a fitting way to recognize veterans.
– Col. Morgan
To Health Insurance Buyers,
If you do not get your health insurance through an employer, it sounds like this is a year when shopping around could make a real difference.
– Col. Morgan


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Before we get to the album, a series of questions…
Do you like your album art black, white, and red?
Do you renounce the name of Jesus Christ?
Do you pray nightly for total destruction of mankind?
If the answer to all four of these is "yes," then right off the bat you probably already know what to expect from the album art above. Ecuador's Destroyer Attack bring forth an onslaught of war-inducing black/death on their sophomore release, Solve Et Coagula.
Solve Et Coagula by Destroyer Attack
Destroyer Attack do break the mold a bit, kicking off with a high-energy instrumental number to inspire the uncontrollable violent urges required to enjoy such a work. The cleaner production is instantly noted. While clear, it doesn't take away from the grime of the sound. Destroyer Attack aren't hiding behind a barrier of eerie atmosphere either; the riffs are front and center. This makes the record an enjoyable, throw-on-and-go-nuts album, full of headbanging, fist-clenching fury. Take, for example, the third track: "Black Poison Rebirth" contains a driving d-beat section that will have any bald dude with a Blasphemy back patch swinging his imaginary hair back and forth in a frenzy. The furor of mid-range tremolo picking seems to never relent. Screaming solos occasionally cut through, peppering Solve Et Coagula with a bit of variation and spice that cuts through the sweltering barrage of war metal like projectiles screaming down from an apocalyptic skyline.
There aren't a whole lot of surprises as the record continues to unfold, but the listener can expect to get exactly what they bargained for. Tracks like "Ectoplasm" and "Necromancy From The Tomb Of The Witch" help to solidify an already strong latter half of the album; Destroyer Attack refuse to let any weakness show as they pummel their way through the album's 37 minutes. Sure, there isn't a whole lot of variation from genre norms here, but Solve Et Coagula doesn't need to be progressive. It just beats the band's brand of black/death metal into the listener without hesitation or restraint.