Leveraging population admixture to explain missing heritability of complex traits

PubMed Central

Zaitlen, Noah; Pasaniuc, Bogdan; Sankararaman, Sriram; Bhatia, Gaurav; Zhang, Jianqi; Gusev, Alexander; Young, Taylor; Tandon, Arti; Pollack, Samuela; Vilhjálmsson, Bjarni J.; Assimes, Themistocles L.; Berndt, Sonja I.; Blot, William J.; Chanock, Stephen; Franceschini, Nora; Goodman, Phyllis G.; He, Jing; Hennis, Anselm JM; Hsing, Ann; Ingles, Sue A.; Isaacs, William; Kittles, Rick A.; Klein, Eric A.; Lange, Leslie A.; Nemesure, Barbara; Patterson, Nick; Reich, David; Rybicki, Benjamin A.; Stanford, Janet L.; Stevens, Victoria L; Strom, Sara S.; Whitsel, Eric A; Witte, John S.; Xu, Jianfeng; Haiman, Christopher; Wilson, James G.; Kooperberg, Charles; Stram, Daniel; Reiner, Alex P.; Tang, Hua; Price, Alkes L.

2014-01-01

Despite recent progress on estimating the heritability explained by genotyped SNPs (hg2), a large gap between hg2 and estimates of total narrow-sense heritability (h2) remains. Explanations for this gap include rare variants, or upward bias in family-based estimates of h2 due to shared environment or epistasis. We estimate h2 from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (hγ2). We show that hγ2 = 2FSTCθ(1−θ)h2, where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We examined 21,497 African Americans from three cohorts, analyzing 13 phenotypes. For height and BMI, we obtained h2 estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of hg2 in these and other data, but smaller than family-based estimates of h2. PMID:25383972

Interindividual variation in DNA methylation at a putative POMC metastable epiallele is associated with obesity

USDA-ARS?s Scientific Manuscript database

The estimated heritability of human BMI is close to 75%, but identified genetic variants explain only a small fraction of interindividual body-weight variation. Inherited epigenetic variants identified in mouse models named "metastable epialleles" could in principle explain this "missing heritabilit...

Integrative Approaches to Understanding the Pathogenic Role of Genetic Variation in Rheumatic Diseases.

PubMed

Laufer, Vincent A; Chen, Jake Y; Langefeld, Carl D; Bridges, S Louis

2017-08-01

The use of high-throughput omics may help to understand the contribution of genetic variants to the pathogenesis of rheumatic diseases. We discuss the concept of missing heritability: that genetic variants do not explain the heritability of rheumatoid arthritis and related rheumatologic conditions. In addition to an overview of how integrative data analysis can lead to novel insights into mechanisms of rheumatic diseases, we describe statistical approaches to prioritizing genetic variants for future functional analyses. We illustrate how analyses of large datasets provide hope for improved approaches to the diagnosis, treatment, and prevention of rheumatic diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Heritability of Problem Drinking and the Genetic Overlap with Personality in a General Population Sample

PubMed Central

de Moor, Marleen H. M.; Vink, Jacqueline M.; van Beek, Jenny H. D. A.; Geels, Lot M.; Bartels, Meike; de Geus, Eco J. C.; Willemsen, Gonneke; Boomsma, Dorret I.

2011-01-01

This study examined the heritability of problem drinking and investigated the phenotypic and genetic relationships between problem drinking and personality. In a sample of 5,870 twins and siblings and 4,420 additional family members from the Netherlands Twin Register. Data on problem drinking (assessed with the AUDIT and CAGE; 12 items) and personality [NEO Five-Factor Inventory (FFI); 60 items] were collected in 2009/2010 by surveys. Confirmatory factor analysis on the AUDIT and CAGE items showed that the items clustered on two separate but highly correlated (r = 0.74) underlying factors. A higher-order factor was extracted that reflected those aspects of problem drinking that are common to the AUDIT and CAGE, which showed a heritability of 40%. The correlations between problem drinking and the five dimensions of personality were small but significant, ranging from 0.06 for Extraversion to −0.12 for Conscientiousness. All personality dimensions (with broad-sense heritabilities between 32 and 55%, and some evidence for non-additive genetic influences) were genetically correlated with problem drinking. The genetic correlations were small to modest (between |0.12| and |0.41|). Future studies with longitudinal data and DNA polymorphisms are needed to determine the biological mechanisms that underlie the genetic link between problem drinking and personality. PMID:22303371

Tic symptom dimensions and their heritabilities in Tourette's syndrome.

PubMed

de Haan, Marcel J; Delucchi, Kevin L; Mathews, Carol M; Cath, Danielle C

2015-06-01

Gilles de la Tourette's syndrome (TS) is both genotypically and phenotypically heterogeneous. Gene-finding strategies have had limited success, possibly because of symptom heterogeneity. This study aimed at specifically investigating heritabilities of tic symptom factors in a relatively large sample of TS patients and family members. Lifetime tic symptom data were collected in 494 diagnosed individuals in two cohorts of TS patients from the USA (n=273) and the Netherlands (n=221), and in 351 Dutch family members. Item-level factor analysis, using a tetrachoric correlation matrix in SAS (v9.2), was carried out on 23 tic symptoms from the Yale Global Tic Severity Scale. Three factors were identified explaining 49% of the total variance: factor 1, complex vocal tics and obscene behaviour; factor 2, body tics; and factor 3, head/neck tics. Using Sequential Oligogenic Linkage Analysis Routine, moderate heritabilities were found for factor 1 (h2r=0.21) and factor 3 (h2r=0.25). Lower heritability was found for overall tic severity (h2r=0.19). Bivariate analyses indicated no genetic associations between tic factors. These findings suggest that (i) three tic factors can be discerned with a distinct underlying genetic architecture and that (ii) considering the low tic heritabilities found, only focusing on the narrow-sense TS phenotype and leaving out comorbidities that are part of the broader sense tic phenotype may lead to missing heritability. Although these findings need replication in larger independent samples, they might have consequences for future genetic studies in TS.

Searching for missing heritability: Designing rare variant association studies

PubMed Central

Zuk, Or; Schaffner, Stephen F.; Samocha, Kaitlin; Do, Ron; Hechter, Eliana; Kathiresan, Sekar; Daly, Mark J.; Neale, Benjamin M.; Sunyaev, Shamil R.; Lander, Eric S.

2014-01-01

Genetic studies have revealed thousands of loci predisposing to hundreds of human diseases and traits, revealing important biological pathways and defining novel therapeutic hypotheses. However, the genes discovered to date typically explain less than half of the apparent heritability. Because efforts have largely focused on common genetic variants, one hypothesis is that much of the missing heritability is due to rare genetic variants. Studies of common variants are typically referred to as genomewide association studies, whereas studies of rare variants are often simply called sequencing studies. Because they are actually closely related, we use the terms common variant association study (CVAS) and rare variant association study (RVAS). In this paper, we outline the similarities and differences between RVAS and CVAS and describe a conceptual framework for the design of RVAS. We apply the framework to address key questions about the sample sizes needed to detect association, the relative merits of testing disruptive alleles vs. missense alleles, frequency thresholds for filtering alleles, the value of predictors of the functional impact of missense alleles, the potential utility of isolated populations, the value of gene-set analysis, and the utility of de novo mutations. The optimal design depends critically on the selection coefficient against deleterious alleles and thus varies across genes. The analysis shows that common variant and rare variant studies require similarly large sample collections. In particular, a well-powered RVAS should involve discovery sets with at least 25,000 cases, together with a substantial replication set. PMID:24443550

Negligible impact of rare autoimmune-locus coding-region variants on missing heritability.

PubMed

Hunt, Karen A; Mistry, Vanisha; Bockett, Nicholas A; Ahmad, Tariq; Ban, Maria; Barker, Jonathan N; Barrett, Jeffrey C; Blackburn, Hannah; Brand, Oliver; Burren, Oliver; Capon, Francesca; Compston, Alastair; Gough, Stephen C L; Jostins, Luke; Kong, Yong; Lee, James C; Lek, Monkol; MacArthur, Daniel G; Mansfield, John C; Mathew, Christopher G; Mein, Charles A; Mirza, Muddassar; Nutland, Sarah; Onengut-Gumuscu, Suna; Papouli, Efterpi; Parkes, Miles; Rich, Stephen S; Sawcer, Steven; Satsangi, Jack; Simmonds, Matthew J; Trembath, Richard C; Walker, Neil M; Wozniak, Eva; Todd, John A; Simpson, Michael A; Plagnol, Vincent; van Heel, David A

2013-06-13

Genome-wide association studies (GWAS) have identified common variants of modest-effect size at hundreds of loci for common autoimmune diseases; however, a substantial fraction of heritability remains unexplained, to which rare variants may contribute. To discover rare variants and test them for association with a phenotype, most studies re-sequence a small initial sample size and then genotype the discovered variants in a larger sample set. This approach fails to analyse a large fraction of the rare variants present in the entire sample set. Here we perform simultaneous amplicon-sequencing-based variant discovery and genotyping for coding exons of 25 GWAS risk genes in 41,911 UK residents of white European origin, comprising 24,892 subjects with six autoimmune disease phenotypes and 17,019 controls, and show that rare coding-region variants at known loci have a negligible role in common autoimmune disease susceptibility. These results do not support the rare-variant synthetic genome-wide-association hypothesis (in which unobserved rare causal variants lead to association detected at common tag variants). Many known autoimmune disease risk loci contain multiple, independently associated, common and low-frequency variants, and so genes at these loci are a priori stronger candidates for harbouring rare coding-region variants than other genes. Our data indicate that the missing heritability for common autoimmune diseases may not be attributable to the rare coding-region variant portion of the allelic spectrum, but perhaps, as others have proposed, may be a result of many common-variant loci of weak effect.

How to improve breeding value prediction for feed conversion ratio in the case of incomplete longitudinal body weights.

PubMed

Tran, V H Huynh; Gilbert, H; David, I

2017-01-01

With the development of automatic self-feeders, repeated measurements of feed intake are becoming easier in an increasing number of species. However, the corresponding BW are not always recorded, and these missing values complicate the longitudinal analysis of the feed conversion ratio (FCR). Our aim was to evaluate the impact of missing BW data on estimations of the genetic parameters of FCR and ways to improve the estimations. On the basis of the missing BW profile in French Large White pigs (male pigs weighed weekly, females and castrated males weighed monthly), we compared 2 different ways of predicting missing BW, 1 using a Gompertz model and 1 using a linear interpolation. For the first part of the study, we used 17,398 weekly records of BW and feed intake recorded over 16 consecutive weeks in 1,222 growing male pigs. We performed a simulation study on this data set to mimic missing BW values according to the pattern of weekly proportions of incomplete BW data in females and castrated males. The FCR was then computed for each week using observed data (obser_FCR), data with missing BW (miss_FCR), data with BW predicted using a Gompertz model (Gomp_FCR), and data with BW predicted by linear interpolation (interp_FCR). Heritability (h) was estimated, and the EBV was predicted for each repeated FCR using a random regression model. In the second part of the study, the full data set (males with their complete BW records, castrated males and females with missing BW) was analyzed using the same methods (miss_FCR, Gomp_FCR, and interp_FCR). Results of the simulation study showed that h were overestimated in the case of missing BW and that predicting BW using a linear interpolation provided a more accurate estimation of h and of EBV than a Gompertz model. Over 100 simulations, the correlation between obser_EBV and interp_EBV, Gomp_EBV, and miss_EBV was 0.93 ± 0.02, 0.91 ± 0.01, and 0.79 ± 0.04, respectively. The heritabilities obtained with the full data set were quite similar for miss_FCR, Gomp_FCR, and interp_FCR. In conclusion, when the proportion of missing BW is high, genetic parameters of FCR are not well estimated. In French Large White pigs, in the growing period extending from d 65 to 168, prediction of missing BW using a Gompertz growth model slightly improved the estimations, but the linear interpolation improved the estimation to a greater extent. This result is due to the linear rather than sigmoidal increase in BW over the study period.

Heritable Endosymbionts of Drosophila

PubMed Central

Mateos, Mariana; Castrezana, Sergio J.; Nankivell, Becky J.; Estes, Anne M.; Markow, Therese A.; Moran, Nancy A.

2006-01-01

Although heritable microorganisms are increasingly recognized as widespread in insects, no systematic screens for such symbionts have been conducted in Drosophila species (the primary insect genetic models for studies of evolution, development, and innate immunity). Previous efforts screened relatively few Drosophila lineages, mainly for Wolbachia. We conducted an extensive survey of potentially heritable endosymbionts from any bacterial lineage via PCR screens of mature ovaries in 181 recently collected fly strains representing 35 species from 11 species groups. Due to our fly sampling methods, however, we are likely to have missed fly strains infected with sex ratio-distorting endosymbionts. Only Wolbachia and Spiroplasma, both widespread in insects, were confirmed as symbionts. These findings indicate that in contrast to some other insect groups, other heritable symbionts are uncommon in Drosophila species, possibly reflecting a robust innate immune response that eliminates many bacteria. A more extensive survey targeted these two symbiont types through diagnostic PCR in 1225 strains representing 225 species from 32 species groups. Of these, 19 species were infected by Wolbachia while only 3 species had Spiroplasma. Several new strains of Wolbachia and Spiroplasma were discovered, including ones divergent from any reported to date. The phylogenetic distribution of Wolbachia and Spiroplasma in Drosophila is discussed. PMID:16783009

Identification of Rare Variants in TNNI3 with Atrial Fibrillation in a Chinese GeneID Population

PubMed Central

Wang, Chuchu; Wu, Manman; Qian, Jin; Li, Bin; Tu, Xin; Xu, Chengqi; Li, Sisi; Chen, Shanshan; Zhao, Yuanyuan; Huang, Yufeng; Shi, Lisong; Cheng, Xiang; Liao, Yuhua; Chen, Qiuyun; Xia, Yunlong; Yao, Wei; Wu, Gang; Cheng, Mian; Wang, Qing K.

2015-01-01

Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as ‘missing heritability’. One potential cause for ‘missing heritability’ is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by 5-fold and doubles risk of heart failure and sudden death. Here we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1,583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1,127 unrelated AF patients and 1,583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1,583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggests that rare TNNI3 variants are associated with AF (P=0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability. PMID:26169204

Beyond DNA: integrating inclusive inheritance into an extended theory of evolution.

PubMed

Danchin, Étienne; Charmantier, Anne; Champagne, Frances A; Mesoudi, Alex; Pujol, Benoit; Blanchet, Simon

2011-06-17

Many biologists are calling for an 'extended evolutionary synthesis' that would 'modernize the modern synthesis' of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions.

Integrative Bayesian variable selection with gene-based informative priors for genome-wide association studies.

PubMed

Zhang, Xiaoshuai; Xue, Fuzhong; Liu, Hong; Zhu, Dianwen; Peng, Bin; Wiemels, Joseph L; Yang, Xiaowei

2014-12-10

Genome-wide Association Studies (GWAS) are typically designed to identify phenotype-associated single nucleotide polymorphisms (SNPs) individually using univariate analysis methods. Though providing valuable insights into genetic risks of common diseases, the genetic variants identified by GWAS generally account for only a small proportion of the total heritability for complex diseases. To solve this "missing heritability" problem, we implemented a strategy called integrative Bayesian Variable Selection (iBVS), which is based on a hierarchical model that incorporates an informative prior by considering the gene interrelationship as a network. It was applied here to both simulated and real data sets. Simulation studies indicated that the iBVS method was advantageous in its performance with highest AUC in both variable selection and outcome prediction, when compared to Stepwise and LASSO based strategies. In an analysis of a leprosy case-control study, iBVS selected 94 SNPs as predictors, while LASSO selected 100 SNPs. The Stepwise regression yielded a more parsimonious model with only 3 SNPs. The prediction results demonstrated that the iBVS method had comparable performance with that of LASSO, but better than Stepwise strategies. The proposed iBVS strategy is a novel and valid method for Genome-wide Association Studies, with the additional advantage in that it produces more interpretable posterior probabilities for each variable unlike LASSO and other penalized regression methods.

Comparing estimates of genetic variance across different relationship models.

PubMed

Legarra, Andres

2016-02-01

Use of relationships between individuals to estimate genetic variances and heritabilities via mixed models is standard practice in human, plant and livestock genetics. Different models or information for relationships may give different estimates of genetic variances. However, comparing these estimates across different relationship models is not straightforward as the implied base populations differ between relationship models. In this work, I present a method to compare estimates of variance components across different relationship models. I suggest referring genetic variances obtained using different relationship models to the same reference population, usually a set of individuals in the population. Expected genetic variance of this population is the estimated variance component from the mixed model times a statistic, Dk, which is the average self-relationship minus the average (self- and across-) relationship. For most typical models of relationships, Dk is close to 1. However, this is not true for very deep pedigrees, for identity-by-state relationships, or for non-parametric kernels, which tend to overestimate the genetic variance and the heritability. Using mice data, I show that heritabilities from identity-by-state and kernel-based relationships are overestimated. Weighting these estimates by Dk scales them to a base comparable to genomic or pedigree relationships, avoiding wrong comparisons, for instance, "missing heritabilities". Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of correcting missing daily feed intake values on the genetic parameters and estimated breeding values for feeding traits in pigs.

PubMed

Ito, Tetsuya; Fukawa, Kazuo; Kamikawa, Mai; Nikaidou, Satoshi; Taniguchi, Masaaki; Arakawa, Aisaku; Tanaka, Genki; Mikawa, Satoshi; Furukawa, Tsutomu; Hirose, Kensuke

2018-01-01

Daily feed intake (DFI) is an important consideration for improving feed efficiency, but measurements using electronic feeder systems contain many missing and incorrect values. Therefore, we evaluated three methods for correcting missing DFI data (quadratic, orthogonal polynomial, and locally weighted (Loess) regression equations) and assessed the effects of these missing values on the genetic parameters and the estimated breeding values (EBV) for feeding traits. DFI records were obtained from 1622 Duroc pigs, comprising 902 individuals without missing DFI and 720 individuals with missing DFI. The Loess equation was the most suitable method for correcting the missing DFI values in 5-50% randomly deleted datasets among the three equations. Both variance components and heritability for the average DFI (ADFI) did not change because of the missing DFI proportion and Loess correction. In terms of rank correlation and information criteria, Loess correction improved the accuracy of EBV for ADFI compared to randomly deleted cases. These findings indicate that the Loess equation is useful for correcting missing DFI values for individual pigs and that the correction of missing DFI values could be effective for the estimation of breeding values and genetic improvement using EBV for feeding traits. © 2017 The Authors. Animal Science Journal published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Animal Science.

COMPLEXO: identifying the missing heritability of breast cancer via next generation collaboration.

PubMed

Southey, Melissa C; Park, Daniel J; Nguyen-Dumont, Tu; Campbell, Ian; Thompson, Ella; Trainer, Alison H; Chenevix-Trench, Georgia; Simard, Jacques; Dumont, Martine; Soucy, Penny; Thomassen, Mads; Jønson, Lars; Pedersen, Inge S; Hansen, Thomas Vo; Nevanlinna, Heli; Khan, Sofia; Sinilnikova, Olga; Mazoyer, Sylvie; Lesueur, Fabienne; Damiola, Francesca; Schmutzler, Rita; Meindl, Alfons; Hahnen, Eric; Dufault, Michael R; Chris Chan, Tl; Kwong, Ava; Barkardóttir, Rosa; Radice, Paolo; Peterlongo, Paolo; Devilee, Peter; Hilbers, Florentine; Benitez, Javier; Kvist, Anders; Törngren, Therese; Easton, Douglas; Hunter, David; Lindstrom, Sara; Kraft, Peter; Zheng, Wei; Gao, Yu-Tang; Long, Jirong; Ramus, Susan; Feng, Bing-Jian; Weitzel, Jeffrey N; Nathanson, Katherine; Offit, Kenneth; Joseph, Vijai; Robson, Mark; Schrader, Kasmintan; Wang, San; Kim, Yeong C; Lynch, Henry; Snyder, Carrie; Tavtigian, Sean; Neuhausen, Susan; Couch, Fergus J; Goldgar, David E

2013-06-21

Linkage analysis, positional cloning, candidate gene mutation scanning and genome-wide association study approaches have all contributed significantly to our understanding of the underlying genetic architecture of breast cancer. Taken together, these approaches have identified genetic variation that explains approximately 30% of the overall familial risk of breast cancer, implying that more, and likely rarer, genetic susceptibility alleles remain to be discovered.

Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the genetics of lipid lowering drugs and diet network study

USDA-ARS?s Scientific Manuscript database

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing ...

Estimating genetic effects and quantifying missing heritability explained by identified rare-variant associations.

PubMed

Liu, Dajiang J; Leal, Suzanne M

2012-10-05

Next-generation sequencing has led to many complex-trait rare-variant (RV) association studies. Although single-variant association analysis can be performed, it is grossly underpowered. Therefore, researchers have developed many RV association tests that aggregate multiple variant sites across a genetic region (e.g., gene), and test for the association between the trait and the aggregated genotype. After these aggregate tests detect an association, it is only possible to estimate the average genetic effect for a group of RVs. As a result of the "winner's curse," such an estimate can be biased. Although for common variants one can obtain unbiased estimates of genetic parameters by analyzing a replication sample, for RVs it is desirable to obtain unbiased genetic estimates for the study where the association is identified. This is because there can be substantial heterogeneity of RV sites and frequencies even among closely related populations. In order to obtain an unbiased estimate for aggregated RV analysis, we developed bootstrap-sample-split algorithms to reduce the bias of the winner's curse. The unbiased estimates are greatly important for understanding the population-specific contribution of RVs to the heritability of complex traits. We also demonstrate both theoretically and via simulations that for aggregate RV analysis the genetic variance for a gene or region will always be underestimated, sometimes substantially, because of the presence of noncausal variants or because of the presence of causal variants with effects of different magnitudes or directions. Therefore, even if RVs play a major role in the complex-trait etiologies, a portion of the heritability will remain missing, and the contribution of RVs to the complex-trait etiologies will be underestimated. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

An Evolutionary Perspective on Epistasis and the Missing Heritability

PubMed Central

Hemani, Gibran; Knott, Sara; Haley, Chris

2013-01-01

The relative importance between additive and non-additive genetic variance has been widely argued in quantitative genetics. By approaching this question from an evolutionary perspective we show that, while additive variance can be maintained under selection at a low level for some patterns of epistasis, the majority of the genetic variance that will persist is actually non-additive. We propose that one reason that the problem of the “missing heritability” arises is because the additive genetic variation that is estimated to be contributing to the variance of a trait will most likely be an artefact of the non-additive variance that can be maintained over evolutionary time. In addition, it can be shown that even a small reduction in linkage disequilibrium between causal variants and observed SNPs rapidly erodes estimates of epistatic variance, leading to an inflation in the perceived importance of additive effects. We demonstrate that the perception of independent additive effects comprising the majority of the genetic architecture of complex traits is biased upwards and that the search for causal variants in complex traits under selection is potentially underpowered by parameterising for additive effects alone. Given dense SNP panels the detection of causal variants through genome-wide association studies may be improved by searching for epistatic effects explicitly. PMID:23509438

Development and genetics of brain temporal stability related to attention problems in adolescent twins.

PubMed

Smit, Dirk J A; Anokhin, Andrey P

2017-05-01

The brain continuously develops and reorganizes to support an expanding repertoire of behaviors and increasingly complex cognition. These processes may, however, also result in the appearance or disappearance of specific neurodevelopmental disorders such as attention problems. To investigate whether brain activity changed during adolescence, how genetics shape this change, and how these changes were related to attention problems, we measured EEG activity in 759 twins and siblings, assessed longitudinally in four waves (12, 14, 16, and 18years of age). Attention problems were assessed with the SWAN at waves 12, 14, and 16. To characterize functional brain development, we used a measure of temporal stability (TS) of brain oscillations over the recording time of 5min reflecting the tendency of a brain to maintain the same oscillatory state for longer or shorter periods. Increased TS may reflect the brain's tendency to maintain stability, achieve focused attention, and thus reduce "mind wandering" and attention problems. The results indicate that brain TS is increased across the scalp from 12 to 18. TS showed large individual differences that were heritable. Change in TS (alpha oscillations) was heritable between 12 and 14 and between 14 and 16 for the frontal brain areas. Absolute levels of brain TS at each wave were positively correlated with attention problems but not significantly. High and low attention problems subjects showed different developmental trajectories in TS, which was significant in a cluster of frontal leads. These results indicate that trajectories in brain TS development are a biomarker for the developing brain. TS in brain oscillations is highly heritable, and age-related change in TS is also heritable in selected brain areas. These results suggest that high and low attention problems subjects are at different stages of brain development. Copyright © 2016. Published by Elsevier B.V.

The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence.

PubMed

Krapohl, Eva; Rimfeld, Kaili; Shakeshaft, Nicholas G; Trzaskowski, Maciej; McMillan, Andrew; Pingault, Jean-Baptiste; Asbury, Kathryn; Harlaar, Nicole; Kovas, Yulia; Dale, Philip S; Plomin, Robert

2014-10-21

Because educational achievement at the end of compulsory schooling represents a major tipping point in life, understanding its causes and correlates is important for individual children, their families, and society. Here we identify the general ingredients of educational achievement using a multivariate design that goes beyond intelligence to consider a wide range of predictors, such as self-efficacy, personality, and behavior problems, to assess their independent and joint contributions to educational achievement. We use a genetically sensitive design to address the question of why educational achievement is so highly heritable. We focus on the results of a United Kingdom-wide examination, the General Certificate of Secondary Education (GCSE), which is administered at the end of compulsory education at age 16. GCSE scores were obtained for 13,306 twins at age 16, whom we also assessed contemporaneously on 83 scales that were condensed to nine broad psychological domains, including intelligence, self-efficacy, personality, well-being, and behavior problems. The mean of GCSE core subjects (English, mathematics, science) is more heritable (62%) than the nine predictor domains (35-58%). Each of the domains correlates significantly with GCSE results, and these correlations are largely mediated genetically. The main finding is that, although intelligence accounts for more of the heritability of GCSE than any other single domain, the other domains collectively account for about as much GCSE heritability as intelligence. Together with intelligence, these domains account for 75% of the heritability of GCSE. We conclude that the high heritability of educational achievement reflects many genetically influenced traits, not just intelligence.

The high heritability of educational achievement reflects many genetically influenced traits, not just intelligence

PubMed Central

Krapohl, Eva; Rimfeld, Kaili; Shakeshaft, Nicholas G.; Trzaskowski, Maciej; McMillan, Andrew; Pingault, Jean-Baptiste; Asbury, Kathryn; Harlaar, Nicole; Kovas, Yulia; Dale, Philip S.; Plomin, Robert

2014-01-01

Because educational achievement at the end of compulsory schooling represents a major tipping point in life, understanding its causes and correlates is important for individual children, their families, and society. Here we identify the general ingredients of educational achievement using a multivariate design that goes beyond intelligence to consider a wide range of predictors, such as self-efficacy, personality, and behavior problems, to assess their independent and joint contributions to educational achievement. We use a genetically sensitive design to address the question of why educational achievement is so highly heritable. We focus on the results of a United Kingdom-wide examination, the General Certificate of Secondary Education (GCSE), which is administered at the end of compulsory education at age 16. GCSE scores were obtained for 13,306 twins at age 16, whom we also assessed contemporaneously on 83 scales that were condensed to nine broad psychological domains, including intelligence, self-efficacy, personality, well-being, and behavior problems. The mean of GCSE core subjects (English, mathematics, science) is more heritable (62%) than the nine predictor domains (35–58%). Each of the domains correlates significantly with GCSE results, and these correlations are largely mediated genetically. The main finding is that, although intelligence accounts for more of the heritability of GCSE than any other single domain, the other domains collectively account for about as much GCSE heritability as intelligence. Together with intelligence, these domains account for 75% of the heritability of GCSE. We conclude that the high heritability of educational achievement reflects many genetically influenced traits, not just intelligence. PMID:25288728

Large-Scale Interaction Effects Reveal Missing Heritability in Schizophrenia, Bipolar Disorder and Posttraumatic Stress Disorder

DTIC Science & Technology

2017-04-11

polymorphisms (SNPs) reached genome-wide significance. In contrast, when SNPs were selected in groups ( containing up to thousands each) and the collective...the underlying genetic factors has been challen- ging because of high polygenicity, necessitating large sample sizes in meta-analyses.4 Possible ways...partners simultaneously considered beyond SNP pairs by using the regularized inference of high -dimensional interactions within large SNP groups. Over

Editorial: Illuminating the dark matter of developmental neuropsychiatric genetics - strategic focus for future research in child psychology and psychiatry.

PubMed

Lesch, Klaus-Peter

2014-03-01

Research on genetic factors influencing cognitive and behavioural traits or which are central to the aetiology of neuropsychiatric diseases has been complicated by a furtive discrepancy between high heritability estimates and a scarcity of replicable gene-disorder associations. This 'missing heritability' has been either euphemised as the 'dark matter' of gene-trait association or aggravated as the 'looming crisis in behavioural genetics'. Nevertheless, in recognising the importance of this topic for our understanding of child psychiatric conditions and highlighting its commitment to the field, the Journal of Child Psychology and Psychiatry (JCPP) has for the first time appointed an editor with special responsibility for molecular (epi)genetics. © 2014 The Authors. Journal of Child Psychology and Psychiatry. © 2014 Association for Child and Adolescent Mental Health.

Gene-Environment Interactions in Asthma: Genetic and Epigenetic Effects.

PubMed

Lee, Jong-Uk; Kim, Jeong Dong; Park, Choon-Sik

2015-07-01

Over the past three decades, a large number of genetic studies have been aimed at finding genetic variants associated with the risk of asthma, applying various genetic and genomic approaches including linkage analysis, candidate gene polymorphism studies, and genome-wide association studies (GWAS). However, contrary to general expectation, even single nucleotide polymorphisms (SNPs) discovered by GWAS failed to fully explain the heritability of asthma. Thus, application of rare allele polymorphisms in well defined phenotypes and clarification of environmental factors have been suggested to overcome the problem of 'missing' heritability. Such factors include allergens, cigarette smoke, air pollutants, and infectious agents during pre- and post-natal periods. The first and simplest interaction between a gene and the environment is a candidate interaction of both a well known gene and environmental factor in a direct physical or chemical interaction such as between CD14 and endotoxin or between HLA and allergens. Several GWAS have found environmental interactions with occupational asthma, aspirin exacerbated respiratory disease, tobacco smoke-related airway dysfunction, and farm-related atopic diseases. As one of the mechanisms behind gene-environment interaction is epigenetics, a few studies on DNA CpG methylation have been reported on subphenotypes of asthma, pitching the exciting idea that it may be possible to intervene at the junction between the genome and the environment. Epigenetic studies are starting to include data from clinical samples, which will make them another powerful tool for re-search on gene-environment interactions in asthma.

A powerful score-based test statistic for detecting gene-gene co-association.

PubMed

Xu, Jing; Yuan, Zhongshang; Ji, Jiadong; Zhang, Xiaoshuai; Li, Hongkai; Wu, Xuesen; Xue, Fuzhong; Liu, Yanxun

2016-01-29

The genetic variants identified by Genome-wide association study (GWAS) can only account for a small proportion of the total heritability for complex disease. The existence of gene-gene joint effects which contains the main effects and their co-association is one of the possible explanations for the "missing heritability" problems. Gene-gene co-association refers to the extent to which the joint effects of two genes differ from the main effects, not only due to the traditional interaction under nearly independent condition but the correlation between genes. Generally, genes tend to work collaboratively within specific pathway or network contributing to the disease and the specific disease-associated locus will often be highly correlated (e.g. single nucleotide polymorphisms (SNPs) in linkage disequilibrium). Therefore, we proposed a novel score-based statistic (SBS) as a gene-based method for detecting gene-gene co-association. Various simulations illustrate that, under different sample sizes, marginal effects of causal SNPs and co-association levels, the proposed SBS has the better performance than other existed methods including single SNP-based and principle component analysis (PCA)-based logistic regression model, the statistics based on canonical correlations (CCU), kernel canonical correlation analysis (KCCU), partial least squares path modeling (PLSPM) and delta-square (δ (2)) statistic. The real data analysis of rheumatoid arthritis (RA) further confirmed its advantages in practice. SBS is a powerful and efficient gene-based method for detecting gene-gene co-association.

Will Big Data Close the Missing Heritability Gap?

PubMed

Kim, Hwasoon; Grueneberg, Alexander; Vazquez, Ana I; Hsu, Stephen; de Los Campos, Gustavo

2017-11-01

Despite the important discoveries reported by genome-wide association (GWA) studies, for most traits and diseases the prediction R-squared (R-sq.) achieved with genetic scores remains considerably lower than the trait heritability. Modern biobanks will soon deliver unprecedentedly large biomedical data sets: Will the advent of big data close the gap between the trait heritability and the proportion of variance that can be explained by a genomic predictor? We addressed this question using Bayesian methods and a data analysis approach that produces a surface response relating prediction R-sq. with sample size and model complexity ( e.g. , number of SNPs). We applied the methodology to data from the interim release of the UK Biobank. Focusing on human height as a model trait and using 80,000 records for model training, we achieved a prediction R-sq. in testing ( n = 22,221) of 0.24 (95% C.I.: 0.23-0.25). Our estimates show that prediction R-sq. increases with sample size, reaching an estimated plateau at values that ranged from 0.1 to 0.37 for models using 500 and 50,000 (GWA-selected) SNPs, respectively. Soon much larger data sets will become available. Using the estimated surface response, we forecast that larger sample sizes will lead to further improvements in prediction R-sq. We conclude that big data will lead to a substantial reduction of the gap between trait heritability and the proportion of interindividual differences that can be explained with a genomic predictor. However, even with the power of big data, for complex traits we anticipate that the gap between prediction R-sq. and trait heritability will not be fully closed. Copyright © 2017 by the Genetics Society of America.

Will Big Data Close the Missing Heritability Gap?

PubMed Central

Kim, Hwasoon; Grueneberg, Alexander; Vazquez, Ana I.; Hsu, Stephen; de los Campos, Gustavo

2017-01-01

Despite the important discoveries reported by genome-wide association (GWA) studies, for most traits and diseases the prediction R-squared (R-sq.) achieved with genetic scores remains considerably lower than the trait heritability. Modern biobanks will soon deliver unprecedentedly large biomedical data sets: Will the advent of big data close the gap between the trait heritability and the proportion of variance that can be explained by a genomic predictor? We addressed this question using Bayesian methods and a data analysis approach that produces a surface response relating prediction R-sq. with sample size and model complexity (e.g., number of SNPs). We applied the methodology to data from the interim release of the UK Biobank. Focusing on human height as a model trait and using 80,000 records for model training, we achieved a prediction R-sq. in testing (n = 22,221) of 0.24 (95% C.I.: 0.23–0.25). Our estimates show that prediction R-sq. increases with sample size, reaching an estimated plateau at values that ranged from 0.1 to 0.37 for models using 500 and 50,000 (GWA-selected) SNPs, respectively. Soon much larger data sets will become available. Using the estimated surface response, we forecast that larger sample sizes will lead to further improvements in prediction R-sq. We conclude that big data will lead to a substantial reduction of the gap between trait heritability and the proportion of interindividual differences that can be explained with a genomic predictor. However, even with the power of big data, for complex traits we anticipate that the gap between prediction R-sq. and trait heritability will not be fully closed. PMID:28893854

Genetics of nonsyndromic obesity.

PubMed

Lee, Yung Seng

2013-12-01

Common obesity is widely regarded as a complex, multifactorial trait influenced by the 'obesogenic' environment, sedentary behavior, and genetic susceptibility contributed by common and rare genetic variants. This review describes the recent advances in understanding the role of genetics in obesity. New susceptibility loci and genetic variants are being uncovered, but the collective effect is relatively small and could not explain most of the BMI heritability. Yet-to-be identified common and rare variants, epistasis, and heritable epigenetic changes may account for part of the 'missing heritability'. Evidence is emerging about the role of epigenetics in determining obesity susceptibility, mediating developmental plasticity, which confers obesity risk from early life experiences. Genetic prediction scores derived from selected genetic variants, and also differential DNA methylation levels and methylation scores, have been shown to correlate with measures of obesity and response to weight loss intervention. Genetic variants, which confer susceptibility to obesity-related morbidities like nonalcoholic fatty liver disease, were also discovered recently. We can expect discovery of more rare genetic variants with the advent of whole exome and genome sequencing, and also greater understanding of epigenetic mechanisms by which environment influences genetic expression and which mediate the gene-environment interaction.

[Implications in primary health care of medical genetics and genomic in type 2 diabetes mellitus].

PubMed

Ramirez-Garcia, Sergio Alberto; Cabrera-Pivaral, Carlos E; Huacuja-Ruiz, Luis; Flores-Alvarado, Luis Javier; Pérez-García, Guillermo; González-Rico, José Luis; López-Velázquez, Alma; Topete-González, Luz Rosalba; Rosales-Góme, Roberto Carlos; Candelario-Mejía, Gerardo; Villa-Ruano, Nemesio

2013-01-01

Type 2 diabetes mellitus is a complex disease and a global health problem. Therefore, the first level of health care should handle the approaches of medical genetics and genomics to reduce its incidence. The aim is to present perspectives analyzed by our group in two areas of genetics and its clinical application. Emphasis is placed on the coexistence of several genetic forms clinically detectable in patients with diabetes, missing heritability associated with low penetrance, and epigenomics mechanism. It is discussed the effect of genetic variation associated with resistance to insulin, beta-cell dysfunction, shaft incretin, and other points of interest, such as thrifty genotype hypothesis, conformational disease, genetically unknown foods, phenocopies as clinically silent hypercortisolism, molecular phytopharmacology in the clinical management. Finally, the result was displayed in the Mexican population from genetic studies and new findings of clinical importance, such as involvement of melatonin and effect of variations in the number of copies in a genomic region.

The genetics of Alzheimer disease: back to the future.

PubMed

Bertram, Lars; Lill, Christina M; Tanzi, Rudolph E

2010-10-21

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

Genetic variation in IBD: progress, clues to pathogenesis and possible clinical utility

PubMed Central

Ye, Byong Duk; McGovern, Dermot P.B.

2016-01-01

Epidemiological and clinical studies have suggested that the pathogenesis of inflammatory bowel disease (IBD) is strongly influenced by genetic predisposition. Beyond the limitations of linkage analysis, multiple genome-wide association studies, their meta-analyses, and targeted genotyping array techniques have broadened our understanding of the genetic architecture of IBD. Currently, over 200 single nucleotide polymorphisms are known to be associated with susceptibility to IBD and through functional analysis of genes and loci, a substantial proportion of pathophysiologic mechanisms have been revealed. However, because only a modest fraction of predicted heritability can be explained by known genes/loci, additional strategies are needed including the identification of rare variants with large effect sizes to help explain the missing heritability. Considerable progress is also being made on applying outcomes of genetic research in diagnostics, classification, prognostics, and the development of new therapeutics of IBD. PMID:27156530

The genetics of human obesity.

PubMed

Xia, Qianghua; Grant, Struan F A

2013-04-01

It has long been known that there is a genetic component to obesity, and that characterizing this underlying factor would likely offer the possibility of better intervention in the future. Monogenic obesity has proved to be relatively straightforward, with a combination of linkage analysis and mouse models facilitating the identification of multiple genes. In contrast, genome-wide association studies have successfully revealed a variety of genetic loci associated with the more common form of obesity, allowing for very strong consensus on the underlying genetic architecture of the phenotype for the first time. Although a number of significant findings have been made, it appears that very little of the apparent heritability of body mass index has actually been explained to date. New approaches for data analyses and advances in technology will be required to uncover the elusive missing heritability, and to aid in the identification of the key causative genetic underpinnings of obesity. © 2013 New York Academy of Sciences.

Blood Transcriptomics and Metabolomics for Personalized Medicine

DTIC Science & Technology

2015-10-31

the network by taking addi- tional information as priors. For example, genes with cis-eQTLs (cis means locally acting on a genomic sequence ) could be...Lander ES. Initial impact of the sequencing of the human genome . Nature 2011; 470(7333):187–97. [9] Manolio TA, et al. Finding the missing heritability of...2010;6(2). [80] Hoffman JM, et al. Effects of age, sex, and genotype on high-sensitivity metabolomic profiles in the fruit fly, Drosophila melanogaster

Optic Nerve Hypoplasia Syndrome: A Review of the Epidemiology and Clinical Associations

PubMed Central

Garcia-Filion, Pamela; Borchert, Mark

2013-01-01

Opinion statement Background Optic nerve hypoplasia (ONH) has developed into a leading cause of congenital blindness. The frequently associated features of hypopituitarism and absent septum pellucidum were felt to have embryonic linkage as “septo-optic dysplasia” or “de Morsier’s syndrome.” More recent studies have suggested these associations are independent of one another. This review provides an assessment of the historical and recent evidence linking neuroradiologic, endocrinologic and developmental morbidity in patients with ONH. The prenatal risk factors, heritability, and genetic mutations associated with ONH are described. Results Recognition of the critical association of ONH with hypopituitarism should be attributed to William Hoyt, not Georges de Morsier. De Morsier never described a case of ONH or recognized its association with hypopituitarism or missing septum pellucidum. Hypopituitarism is caused by hypothalamic dysfunction. This, and other more recently identified associations with ONH, such as developmental delay and autism, are independent of septum pellucidum development. Other common neuroradiographic associations such as corpus callosum hypoplasia, gyrus dysplasia, and cortical heterotopia may have prognostic significance. The predominant prenatal risk factors for ONH are primiparity and young maternal age. Presumed risk factors such as prenatal exposure to drugs and alcohol are not supported by scrutiny of the literature. Heritability and identified gene mutations in cases of ONH are rare. Conclusion Children with ONH require monitoring for many systemic, developmental, and even life-threatening problems independent of the severity of ONH and presence of brain malformations including abnormalities of the septum pellucidum. “Septo-optic dysplasia” and “de Morsier’s syndrome” are historically inaccurate and clinically misleading terms. PMID:23233151

The etiology of behavior problems in 7-year-old twins: substantial genetic influence and negligible shared environmental influence for parent ratings and ratings by same and different teachers.

PubMed

Saudino, Kimberly J; Ronald, Angelica; Plomin, Robert

2005-02-01

Parent ratings of behavior problems in childhood show substantial genetic influence and modest shared environmental influence. However, few studies have compared these results to teacher ratings and no previous studies have compared same-teacher ratings to different-teacher ratings. 3,714 7-year-old twin pairs in the Twins Early Development Study were rated by parents and teachers on the Strengths and Difficulties Questionnaire. Substantial heritability and negligible shared environmental influence were found for data from all three raters for total behavior problems, hyperactivity, prosocial behavior, peer problems, conduct problems, and emotional symptoms. Sex-limitation models revealed similar results for males and females, although there was some evidence for greater heritability for boys, especially when twins were rated by the same teacher.

Comparison of Family History and SNPs for Predicting Risk of Complex Disease

PubMed Central

Do, Chuong B.; Hinds, David A.; Francke, Uta; Eriksson, Nicholas

2012-01-01

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)–based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%–30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history–based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalone disease prediction. On the other hand, we show that, unlike family history, SNP–based tests can reveal extreme likelihood ratios for a relatively large percentage of individuals, thus providing potentially valuable adjunctive evidence in a differential diagnosis. PMID:23071447

The Heritability of Cluster B Personality Disorders Assessed both by Personal Interview and Questionnaire

PubMed Central

Torgersen, Svenn; Myers, John; Reichborn-Kjennerud, Ted; Røysamb, Espen; Kubarych, Thomas S.; Kendler, Kenneth S.

2013-01-01

Whereas the heritability of common personality traits has been firmly established, the results of the few published studies on personality disorders (PDs) are highly divergent, with some studies finding high heredity and others very low. A problem with assessing personality disorders by means of interview is errors connected with interviewer bias. A way to overcome the problem is to use self-report questionnaires in addition to interviews. This study used both interview and questionnaire for assessing DSM-IV Cluster B personality disorders: antisocial personality disorder (APD), borderline (BPD), narcissistic (NPD), and histrionic (HPD). We assessed close to 2,800 twins from the Norwegian Institute of Public Health Twin Panel using a self-report questionnaire and, a few years later, the Structured Interview for DSM-IV Personality (SIDP-IV). Items from the self-report questionnaire that best predicted the PDs captured by the interview were then selected. Measurement models combining questionnaire and interview information were applied and were fitted using Mx. Whereas the heritability of Cluster B PDs assessed by interview was around .30, and around .40–.50 when assessed by self-report questionnaire, the heritability of the convergent latent factor, including information from both interview and self-report questionnaire was .69 for APD, .67 for BPD, .71 for NPD, and .63 for HPD. As is usually found for personality, the effect of shared-in families (familial) environment was zero. In conclusion, when both interview and self-report questionnaire are taken into account, the heritability of Cluster B PD appears to be in the upper range of previous findings for mental disorders. PMID:23281671

The heritability of Cluster B personality disorders assessed both by personal interview and questionnaire.

PubMed

Torgersen, Svenn; Myers, John; Reichborn-Kjennerud, Ted; Røysamb, Espen; Kubarych, Thomas S; Kendler, Kenneth S

2012-12-01

Whereas the heritability of common personality traits has been firmly established, the results of the few published studies on personality disorders (PDs) are highly divergent, with some studies finding high heredity and others very low. A problem with assessing personality disorders by means of interview is errors connected with interviewer bias. A way to overcome the problem is to use self-report questionnaires in addition to interviews. This study used both interview and questionnaire for assessing DSM-IV Cluster B personality disorders: antisocial personality disorder (APD), borderline (BPD), narcissistic (NPD), and histrionic (HPD). We assessed close to 2,800 twins from the Norwegian Institute of Public Health Twin Panel using a self-report questionnaire and, a few years later, the Structured Interview for DSM-IV Personality (SIDP-IV). Items from the self-report questionnaire that best predicted the PDs captured by the interview were then selected. Measurement models combining questionnaire and interview information were applied and were fitted using Mx. Whereas the heritability of Cluster B PDs assessed by interview was around .30, and around .40-.50 when assessed by self-report questionnaire, the heritability of the convergent latent factor, including information from both interview and self-report questionnaire was .69 for APD, .67 for BPD, .71 for NPD, and .63 for HPD. As is usually found for personality, the effect of shared-in families (familial) environment was zero. In conclusion, when both interview and self-report questionnaire are taken into account, the heritability of Cluster B PD appears to be in the upper range of previous findings for mental disorders.

Genetics and intelligence differences: five special findings.

PubMed

Plomin, R; Deary, I J

2015-02-01

Intelligence is a core construct in differential psychology and behavioural genetics, and should be so in cognitive neuroscience. It is one of the best predictors of important life outcomes such as education, occupation, mental and physical health and illness, and mortality. Intelligence is one of the most heritable behavioural traits. Here, we highlight five genetic findings that are special to intelligence differences and that have important implications for its genetic architecture and for gene-hunting expeditions. (i) The heritability of intelligence increases from about 20% in infancy to perhaps 80% in later adulthood. (ii) Intelligence captures genetic effects on diverse cognitive and learning abilities, which correlate phenotypically about 0.30 on average but correlate genetically about 0.60 or higher. (iii) Assortative mating is greater for intelligence (spouse correlations ~0.40) than for other behavioural traits such as personality and psychopathology (~0.10) or physical traits such as height and weight (~0.20). Assortative mating pumps additive genetic variance into the population every generation, contributing to the high narrow heritability (additive genetic variance) of intelligence. (iv) Unlike psychiatric disorders, intelligence is normally distributed with a positive end of exceptional performance that is a model for 'positive genetics'. (v) Intelligence is associated with education and social class and broadens the causal perspectives on how these three inter-correlated variables contribute to social mobility, and health, illness and mortality differences. These five findings arose primarily from twin studies. They are being confirmed by the first new quantitative genetic technique in a century-Genome-wide Complex Trait Analysis (GCTA)-which estimates genetic influence using genome-wide genotypes in large samples of unrelated individuals. Comparing GCTA results to the results of twin studies reveals important insights into the genetic architecture of intelligence that are relevant to attempts to narrow the 'missing heritability' gap.

Genetics and intelligence differences: five special findings

PubMed Central

Plomin, R; Deary, I J

2015-01-01

Intelligence is a core construct in differential psychology and behavioural genetics, and should be so in cognitive neuroscience. It is one of the best predictors of important life outcomes such as education, occupation, mental and physical health and illness, and mortality. Intelligence is one of the most heritable behavioural traits. Here, we highlight five genetic findings that are special to intelligence differences and that have important implications for its genetic architecture and for gene-hunting expeditions. (i) The heritability of intelligence increases from about 20% in infancy to perhaps 80% in later adulthood. (ii) Intelligence captures genetic effects on diverse cognitive and learning abilities, which correlate phenotypically about 0.30 on average but correlate genetically about 0.60 or higher. (iii) Assortative mating is greater for intelligence (spouse correlations ~0.40) than for other behavioural traits such as personality and psychopathology (~0.10) or physical traits such as height and weight (~0.20). Assortative mating pumps additive genetic variance into the population every generation, contributing to the high narrow heritability (additive genetic variance) of intelligence. (iv) Unlike psychiatric disorders, intelligence is normally distributed with a positive end of exceptional performance that is a model for ‘positive genetics'. (v) Intelligence is associated with education and social class and broadens the causal perspectives on how these three inter-correlated variables contribute to social mobility, and health, illness and mortality differences. These five findings arose primarily from twin studies. They are being confirmed by the first new quantitative genetic technique in a century—Genome-wide Complex Trait Analysis (GCTA)—which estimates genetic influence using genome-wide genotypes in large samples of unrelated individuals. Comparing GCTA results to the results of twin studies reveals important insights into the genetic architecture of intelligence that are relevant to attempts to narrow the ‘missing heritability' gap. PMID:25224258

Genome-Wide Association Mapping and Genomic Prediction Elucidate the Genetic Architecture of Morphological Traits in Arabidopsis.

PubMed

Kooke, Rik; Kruijer, Willem; Bours, Ralph; Becker, Frank; Kuhn, André; van de Geest, Henri; Buntjer, Jaap; Doeswijk, Timo; Guerra, José; Bouwmeester, Harro; Vreugdenhil, Dick; Keurentjes, Joost J B

2016-04-01

Quantitative traits in plants are controlled by a large number of genes and their interaction with the environment. To disentangle the genetic architecture of such traits, natural variation within species can be explored by studying genotype-phenotype relationships. Genome-wide association studies that link phenotypes to thousands of single nucleotide polymorphism markers are nowadays common practice for such analyses. In many cases, however, the identified individual loci cannot fully explain the heritability estimates, suggesting missing heritability. We analyzed 349 Arabidopsis accessions and found extensive variation and high heritabilities for different morphological traits. The number of significant genome-wide associations was, however, very low. The application of genomic prediction models that take into account the effects of all individual loci may greatly enhance the elucidation of the genetic architecture of quantitative traits in plants. Here, genomic prediction models revealed different genetic architectures for the morphological traits. Integrating genomic prediction and association mapping enabled the assignment of many plausible candidate genes explaining the observed variation. These genes were analyzed for functional and sequence diversity, and good indications that natural allelic variation in many of these genes contributes to phenotypic variation were obtained. For ACS11, an ethylene biosynthesis gene, haplotype differences explaining variation in the ratio of petiole and leaf length could be identified. © 2016 American Society of Plant Biologists. All Rights Reserved.

Empirical likelihood method for non-ignorable missing data problems.

PubMed

Guan, Zhong; Qin, Jing

2017-01-01

Missing response problem is ubiquitous in survey sampling, medical, social science and epidemiology studies. It is well known that non-ignorable missing is the most difficult missing data problem where the missing of a response depends on its own value. In statistical literature, unlike the ignorable missing data problem, not many papers on non-ignorable missing data are available except for the full parametric model based approach. In this paper we study a semiparametric model for non-ignorable missing data in which the missing probability is known up to some parameters, but the underlying distributions are not specified. By employing Owen (1988)'s empirical likelihood method we can obtain the constrained maximum empirical likelihood estimators of the parameters in the missing probability and the mean response which are shown to be asymptotically normal. Moreover the likelihood ratio statistic can be used to test whether the missing of the responses is non-ignorable or completely at random. The theoretical results are confirmed by a simulation study. As an illustration, the analysis of a real AIDS trial data shows that the missing of CD4 counts around two years are non-ignorable and the sample mean based on observed data only is biased.

Rare Variant Association Test with Multiple Phenotypes

PubMed Central

Lee, Selyeong; Won, Sungho; Kim, Young Jin; Kim, Yongkang; Kim, Bong-Jo; Park, Taesung

2016-01-01

Although genome-wide association studies (GWAS) have now discovered thousands of genetic variants associated with common traits, such variants cannot explain the large degree of “missing heritability,” likely due to rare variants. The advent of next generation sequencing technology has allowed rare variant detection and association with common traits, often by investigating specific genomic regions for rare variant effects on a trait. Although multiply correlated phenotypes are often concurrently observed in GWAS, most studies analyze only single phenotypes, which may lessen statistical power. To increase power, multivariate analyses, which consider correlations between multiple phenotypes, can be used. However, few existing multi-variant analyses can identify rare variants for assessing multiple phenotypes. Here, we propose Multivariate Association Analysis using Score Statistics (MAAUSS), to identify rare variants associated with multiple phenotypes, based on the widely used Sequence Kernel Association Test (SKAT) for a single phenotype. We applied MAAUSS to Whole Exome Sequencing (WES) data from a Korean population of 1,058 subjects, to discover genes associated with multiple traits of liver function. We then assessed validation of those genes by a replication study, using an independent dataset of 3,445 individuals. Notably, we detected the gene ZNF620 among five significant genes. We then performed a simulation study to compare MAAUSS's performance with existing methods. Overall, MAAUSS successfully conserved type 1 error rates and in many cases, had a higher power than the existing methods. This study illustrates a feasible and straightforward approach for identifying rare variants correlated with multiple phenotypes, with likely relevance to missing heritability. PMID:28039885

Heritable influences on behavioural problems from early childhood to mid-adolescence: evidence for genetic stability and innovation.

PubMed

Lewis, G J; Plomin, R

2015-07-01

Although behavioural problems (e.g., anxiety, conduct, hyperactivity, peer problems) are known to be heritable both in early childhood and in adolescence, limited work has examined prediction across these ages, and none using a genetically informative sample. We examined, first, whether parental ratings of behavioural problems (indexed by the Strengths and Difficulties questionnaire) at ages 4, 7, 9, 12, and 16 years were stable across these ages. Second, we examined the extent to which stability reflected genetic or environmental effects through multivariate quantitative genetic analysis on data from a large (n > 3000) population (UK) sample of monozygotic and dizygotic twins. Behavioural problems in early childhood (age 4 years) showed significant associations with the corresponding behavioural problem at all subsequent ages. Moreover, stable genetic influences were observed across ages, indicating that biological bases underlying behavioural problems in adolescence are underpinned by genetic influences expressed as early as age 4 years. However, genetic and environmental innovations were also observed at each age. These observations indicate that genetic factors are important for understanding stable individual differences in behavioural problems across childhood and adolescence, although novel genetic influences also facilitate change in such behaviours.

Genetic variations in the serotonergic system contribute to amygdala volume in humans.

PubMed

Li, Jin; Chen, Chunhui; Wu, Karen; Zhang, Mingxia; Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K; Dong, Qi

2015-01-01

The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63-65% heritability of amygdala structure. To understand the "missing heritability," we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure.

Whole-exome SNP array identifies 15 new susceptibility loci for psoriasis

PubMed Central

Zuo, Xianbo; Sun, Liangdan; Yin, Xianyong; Gao, Jinping; Sheng, Yujun; Xu, Jinhua; Zhang, Jianzhong; He, Chundi; Qiu, Ying; Wen, Guangdong; Tian, Hongqing; Zheng, Xiaodong; Liu, Shengxiu; Wang, Wenjun; Li, Weiran; Cheng, Yuyan; Liu, Longdan; Chang, Yan; Wang, Zaixing; Li, Zenggang; Li, Longnian; Wu, Jianping; Fang, Ling; Shen, Changbing; Zhou, Fusheng; Liang, Bo; Chen, Gang; Li, Hui; Cui, Yong; Xu, Aie; Yang, Xueqin; Hao, Fei; Xu, Limin; Fan, Xing; Li, Yuzhen; Wu, Rina; Wang, Xiuli; Liu, Xiaoming; Zheng, Min; Song, Shunpeng; Ji, Bihua; Fang, Hong; Yu, Jianbin; Sun, Yongxin; Hui, Yan; Zhang, Furen; Yang, Rongya; Yang, Sen; Zhang, Xuejun

2015-01-01

Genome-wide association studies (GWASs) have reproducibly associated ∼40 susceptibility loci with psoriasis. However, the missing heritability is evident and the contributions of coding variants have not yet been systematically evaluated. Here, we present a large-scale whole-exome array analysis for psoriasis consisting of 42,760 individuals. We discover 16 SNPs within 15 new genes/loci associated with psoriasis, including C1orf141, ZNF683, TMC6, AIM2, IL1RL1, CASR, SON, ZFYVE16, MTHFR, CCDC129, ZNF143, AP5B1, SYNE2, IFNGR2 and 3q26.2-q27 (P<5.00 × 10−08). In addition, we also replicate four known susceptibility loci TNIP1, NFKBIA, IL12B and LCE3D–LCE3E. These susceptibility variants identified in the current study collectively account for 1.9% of the psoriasis heritability. The variant within AIM2 is predicted to impact protein structure. Our findings increase the number of genetic risk factors for psoriasis and highlight new and plausible biological pathways in psoriasis. PMID:25854761

Using Stochastic Approximation Techniques to Efficiently Construct Confidence Intervals for Heritability.

PubMed

Schweiger, Regev; Fisher, Eyal; Rahmani, Elior; Shenhav, Liat; Rosset, Saharon; Halperin, Eran

2018-06-22

Estimation of heritability is an important task in genetics. The use of linear mixed models (LMMs) to determine narrow-sense single-nucleotide polymorphism (SNP)-heritability and related quantities has received much recent attention, due of its ability to account for variants with small effect sizes. Typically, heritability estimation under LMMs uses the restricted maximum likelihood (REML) approach. The common way to report the uncertainty in REML estimation uses standard errors (SEs), which rely on asymptotic properties. However, these assumptions are often violated because of the bounded parameter space, statistical dependencies, and limited sample size, leading to biased estimates and inflated or deflated confidence intervals (CIs). In addition, for larger data sets (e.g., tens of thousands of individuals), the construction of SEs itself may require considerable time, as it requires expensive matrix inversions and multiplications. Here, we present FIESTA (Fast confidence IntErvals using STochastic Approximation), a method for constructing accurate CIs. FIESTA is based on parametric bootstrap sampling, and, therefore, avoids unjustified assumptions on the distribution of the heritability estimator. FIESTA uses stochastic approximation techniques, which accelerate the construction of CIs by several orders of magnitude, compared with previous approaches as well as to the analytical approximation used by SEs. FIESTA builds accurate CIs rapidly, for example, requiring only several seconds for data sets of tens of thousands of individuals, making FIESTA a very fast solution to the problem of building accurate CIs for heritability for all data set sizes.

A genome-wide gene–environment interaction analysis for tobacco smoke and lung cancer susceptibility

PubMed Central

Zhang, Ruyang; Chu, Minjie; Zhao, Yang; Wu, Chen; Guo, Huan; Shi, Yongyong; Dai, Juncheng; Wei, Yongyue; Jin, Guangfu; Ma, Hongxia; Dong, Jing; Yi, Honggang; Bai, Jianling; Gong, Jianhang; Sun, Chongqi; Zhu, Meng; Wu, Tangchun; Hu, Zhibin; Lin, Dongxin; Shen, Hongbing; Chen, Feng

2014-01-01

Tobacco smoke is the major environmental risk factor underlying lung carcinogenesis. However, approximately one-tenth smokers develop lung cancer in their lifetime indicating there is significant individual variation in susceptibility to lung cancer. And, the reasons for this are largely unknown. In particular, the genetic variants discovered in genome-wide association studies (GWAS) account for only a small fraction of the phenotypic variations for lung cancer, and gene–environment interactions are thought to explain the missing fraction of disease heritability. The ability to identify smokers at high risk of developing cancer has substantial preventive implications. Thus, we undertook a gene–smoking interaction analysis in a GWAS of lung cancer in Han Chinese population using a two-phase designed case–control study. In the discovery phase, we evaluated all pair-wise (591 370) gene–smoking interactions in 5408 subjects (2331 cases and 3077 controls) using a logistic regression model with covariate adjustment. In the replication phase, promising interactions were validated in an independent population of 3023 subjects (1534 cases and 1489 controls). We identified interactions between two single nucleotide polymorphisms and smoking. The interaction P values are 6.73 × 10− 6 and 3.84 × 10− 6 for rs1316298 and rs4589502, respectively, in the combined dataset from the two phases. An antagonistic interaction (rs1316298–smoking) and a synergetic interaction (rs4589502–smoking) were observed. The two interactions identified in our study may help explain some of the missing heritability in lung cancer susceptibility and present strong evidence for further study of these gene–smoking interactions, which are benefit to intensive screening and smoking cessation interventions. PMID:24658283

Identifying Common Genetic Risk Factors of Diabetic Neuropathies

PubMed Central

Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

2015-01-01

Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

A population genetic interpretation of GWAS findings for human quantitative traits

PubMed Central

Bullaughey, Kevin; Hudson, Richard R.; Sella, Guy

2018-01-01

Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes—notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space. We solve the model for the phenotypic distribution and allelic dynamics at steady state and derive robust, closed-form solutions for summary statistics of the genetic architecture. Our results provide a simple interpretation for missing heritability and why it varies among traits. They predict that the distribution of variances contributed by loci identified in GWASs is well approximated by a simple functional form that depends on a single parameter: the expected contribution to genetic variance of a strongly selected site affecting the trait. We test this prediction against the results of GWASs for height and body mass index (BMI) and find that it fits the data well, allowing us to make inferences about the degree of pleiotropy and mutational target size for these traits. Our findings help to explain why the GWAS for height explains more of the heritable variance than the similarly sized GWAS for BMI and to predict the increase in explained heritability with study sample size. Considering the demographic history of European populations, in which these GWASs were performed, we further find that most of the associations they identified likely involve mutations that arose shortly before or during the Out-of-Africa bottleneck at sites with selection coefficients around s = 10−3. PMID:29547617

Missing, Abducted, Runaway, and Thrownaway Children in America. First Report: Numbers and Characteristics, National Incidence Studies. Executive Summary.

ERIC Educational Resources Information Center

Finkelhor, David; And Others

What has in the past been called the missing children problem is in reality a set of at least five distinct problems, each of which needs to be researched, analyzed, and treated separately. The problems are family abductions, nonfamily abductions, runaways, thrownaways, and lost, injured, or otherwise missing children. Many of the children in at…

Implications of Systematic Nominator Missingness for Peer Nomination Data

ERIC Educational Resources Information Center

Babcock, Ben; Marks, Peter E. L.; van den Berg, Yvonne H. M.; Cillessen, Antonius H. N.

2018-01-01

Missing data are a persistent problem in psychological research. Peer nomination data present a unique missing data problem, because a nominator's nonparticipation results in missing data for other individuals in the study. This study examined the range of effects of systematic nonparticipation on the correlations between peer nomination data when…

Rare genetic variants and the risk of cancer.

PubMed

Bodmer, Walter; Tomlinson, Ian

2010-06-01

There are good reasons to expect that common genetic variants do not explain all of the inherited risk of the common cancers, not least of these being the relatively low proportion of familial relative risk that common cancer SNPs currently explain. One promising source of the unexplained risk is rare, low-penetrance genetic variants, a class that ranges from low-frequency polymorphisms (allele frequency < 5%) through subpolymorphic variants (frequency 0.1-1.0%) to very low frequency or 'private' variants with frequencies of 0.1% or less. Examples of rare cancer variants include breast cancer susceptibility loci CHEK2, BRIP1 and PALB2. There are considerable challenges associated with the discovery and testing of rare predisposition alleles, many of which are illustrated by the issues associated with variants of unknown significance in the Mendelian cancer predisposition genes. However, whilst cost constraints remain, the technological barriers to rare variant discovery and large-scale genotyping no longer exist. If each individual carries many disease-causing rare variants, the so-called missing heritability of cancer might largely be explained. Whether or not rare variants do end up filling the heritability gap, it is imperative to look for them along side common variants.

Genetic variations in the serotonergic system contribute to amygdala volume in humans

PubMed Central

Li, Jin; Chen, Chunhui; Wu, Karen; Zhang, Mingxia; Zhu, Bi; Chen, Chuansheng; Moyzis, Robert K.; Dong, Qi

2015-01-01

The amygdala plays a critical role in emotion processing and psychiatric disorders associated with emotion dysfunction. Accumulating evidence suggests that amygdala structure is modulated by serotonin-related genes. However, there is a gap between the small contributions of single loci (less than 1%) and the reported 63–65% heritability of amygdala structure. To understand the “missing heritability,” we systematically explored the contribution of serotonin genes on amygdala structure at the gene set level. The present study of 417 healthy Chinese volunteers examined 129 representative polymorphisms in genes from multiple biological mechanisms in the regulation of serotonin neurotransmission. A system-level approach using multiple regression analyses identified that nine SNPs collectively accounted for approximately 8% of the variance in amygdala volume. Permutation analyses showed that the probability of obtaining these findings by chance was low (p = 0.043, permuted for 1000 times). Findings showed that serotonin genes contribute moderately to individual differences in amygdala volume in a healthy Chinese sample. These results indicate that the system-level approach can help us to understand the genetic basis of a complex trait such as amygdala structure. PMID:26500508

Introduction to Deep Sequencing and Its Application to Drug Addiction Research with a Focus on Rare Variants

PubMed Central

Wang, Shaolin; Yang, Zhongli; Ma, Jennie Z.; Payne, Thomas J.; Li, Ming D

2013-01-01

Through linkage analysis, candidate gene approach, and genome-wide association studies (GWAS), many genetic susceptibility factors for substance dependence have been discovered, such as the alcohol dehydrogenase gene (ALDH2) for alcohol dependence (AD) and nicotinic acetylcholine receptor (nAChR) subunit variants on chromosomes 8 and 15 for nicotine dependence (ND). However, these confirmed genetic factors contribute only a small portion of the heritability responsible for each addiction. Among many potential factors, rare variants in those identified and unidentified susceptibility genes are supposed to contribute greatly to the missing heritability. Several studies focusing on rare variants have been conducted by taking advantage of next-generation sequencing technologies, which revealed that some rare variants of nAChR subunits are associated with ND in both genetic and functional studies. However, these studies investigated variants for only a small number of genes and need to be expanded to broad regions/genes in a larger population. This review presents an update on recently developed methods for rare-variant identification and association analysis and on studies focused on rare-variant discovery and function related to addictions. PMID:23990377

Effect of inter- and intragenic epistasis on the heritability of oil content in rapeseed (Brassica napus L.).

PubMed

Würschum, Tobias; Maurer, Hans Peter; Dreyer, Felix; Reif, Jochen C

2013-02-01

The loci detected by association mapping which are involved in the expression of important agronomic traits in crops often explain only a small proportion of the total genotypic variance. Here, 17 SNPs derived from 9 candidate genes from the triacylglycerol biosynthetic pathway were studied in an association analysis in a population of 685 diverse elite rapeseed inbred lines. The 685 lines were evaluated for oil content, as well as for glucosinolates, yield, and thousand-kernel weight in field trials at 4 locations. We detected main effects for most of the studied genes illustrating that genetic diversity for oil content can be exploited by the selection of favorable alleles. In addition to main effects, both intergenic and intragenic epistasis was detected that contributes to a considerable amount to the genotypic variance observed for oil content. The proportion of explained genotypic variance was doubled when in addition to main effects epistasis was considered. Therefore, a knowledge-based improvement of oil content in rapeseed should also take such favorable epistatic interactions into account. Our results suggest, that the observed high contribution of epistasis may to some extent explain the missing heritability in genome-wide association studies.

Maternal pre-pregnancy weight and externalising behaviour problems in preschool children: a UK-based twin study.

PubMed

Antoniou, Evangelia E; Fowler, Tom; Reed, Keith; Southwood, Taunton R; McCleery, Joseph P; Zeegers, Maurice P

2014-10-14

To estimate the heritability of child behaviour problems and investigate the association between maternal pre-pregnancy overweight and child behaviour problems in a genetically sensitive design. Observational cross-sectional study. The Twins and Multiple Births Association Heritability Study (TAMBAHS) is an online UK-wide volunteer-based study investigating the development of twins from birth until 5 years of age. A total of 443 (16% of the initial registered members) mothers answered questions on pre-pregnancy weight and their twins' internalising and externalising problems using the Child Behavior Checklist and correcting for important covariates including gestational age, twins' birth weight, age and sex, mother's educational level and smoking (before, during and after pregnancy). The heritability of behaviour problems and their association with maternal pre-pregnancy weight. The genetic analysis suggested that genetic and common environmental factors account for most of the variation in externalising disorders (an ACE model was the most parsimonious with genetic factors (A) explaining 46% (95% CI 33% to 60%) of the variance, common environment (C) explaining 42% (95% CI 27% to 54%) and non-shared environmental factors (E) explaining 13% (95% CI 10% to 16%) of the variance. For internalising problems, a CE model was the most parsimonious model with the common environment explaining 51% (95% CI 44% to 58%) of the variance and non-shared environment explaining 49% (95% CI 42% to 56%) of the variance. Moreover, the regression analysis results suggested that children of overweight mothers showed a trend (OR=1.10, 95% CI 0.58% to 2.06) towards being more aggressive and exhibit externalising behaviours compared to children of normal weight mothers. Maternal pre-pregnancy weight may play a role in children's aggressive behaviour. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Longitudinal data analysis with non-ignorable missing data.

PubMed

Tseng, Chi-hong; Elashoff, Robert; Li, Ning; Li, Gang

2016-02-01

A common problem in the longitudinal data analysis is the missing data problem. Two types of missing patterns are generally considered in statistical literature: monotone and non-monotone missing data. Nonmonotone missing data occur when study participants intermittently miss scheduled visits, while monotone missing data can be from discontinued participation, loss to follow-up, and mortality. Although many novel statistical approaches have been developed to handle missing data in recent years, few methods are available to provide inferences to handle both types of missing data simultaneously. In this article, a latent random effects model is proposed to analyze longitudinal outcomes with both monotone and non-monotone missingness in the context of missing not at random. Another significant contribution of this article is to propose a new computational algorithm for latent random effects models. To reduce the computational burden of high-dimensional integration problem in latent random effects models, we develop a new computational algorithm that uses a new adaptive quadrature approach in conjunction with the Taylor series approximation for the likelihood function to simplify the E-step computation in the expectation-maximization algorithm. Simulation study is performed and the data from the scleroderma lung study are used to demonstrate the effectiveness of this method. © The Author(s) 2012.

Genetic parameters of product quality and hepatic metabolism in fattened mule ducks.

PubMed

Marie-Etancelin, C; Basso, B; Davail, S; Gontier, K; Fernandez, X; Vitezica, Z G; Bastianelli, D; Baéza, E; Bernadet, M-D; Guy, G; Brun, J-M; Legarra, A

2011-03-01

Genetic parameters of traits related to hepatic lipid metabolism, carcass composition, and product quality of overfed mule ducks were estimated on both parental lines of this hybrid: the common duck line for the maternal side and the Muscovy line for the paternal side. The originality of the statistical model was to include simultaneously the additive genetic effect of the common ducks and that of the Muscovy ducks, revealing a greater genetic determinism in common than in Muscovy. Plasma metabolic indicators (glucose, triglyceride, and cholesterol contents) were heritable, in particular at the end of the overfeeding period, and heritabilities increased with the overfeeding stage. Carcass composition traits were highly heritable in the common line, with values ranging from 0.15 for liver weight, 0.21 for carcass weight, and 0.25 for abdominal fat weight to 0.32 for breast muscle weight. Heritabilities of technological outputs were greater for the fatty liver (0.19 and 0.08, respectively, on common and Muscovy sides for liver melting rate) than for the pectoralis major muscle (between 0.02 and 0.05 on both parental sides for cooking losses). Fortunately, the processing industry is mainly facing problems in liver quality, such as too high of a melting rate, than in meat quality. The meat quality appraisal criteria (such as texture and cooking losses), usually dependent on pH and the rate of decline of pH, were also very lowly heritable. This study demonstrated that genetic determinism of meat quality and ability of overfeeding is not similar in the common population and in the Muscovy population; traits related to fattening, muscle development, and BW have heritability values from 2 to 4 times greater on the common line than on the Muscovy line, which is relevant for considering different selection strategies.

Estimation of Item Response Theory Parameters in the Presence of Missing Data

ERIC Educational Resources Information Center

Finch, Holmes

2008-01-01

Missing data are a common problem in a variety of measurement settings, including responses to items on both cognitive and affective assessments. Researchers have shown that such missing data may create problems in the estimation of item difficulty parameters in the Item Response Theory (IRT) context, particularly if they are ignored. At the same…

Prevalence and heritability of body dysmorphic symptoms in adolescents and young adults: a population-based nationwide twin study.

PubMed

Enander, Jesper; Ivanov, Volen Z; Mataix-Cols, David; Kuja-Halkola, Ralf; Ljótsson, Brjánn; Lundström, Sebastian; Pérez-Vigil, Ana; Monzani, Benedetta; Lichtenstein, Paul; Rück, Christian

2018-02-28

Body dysmorphic disorder (BDD) usually begins during adolescence but little is known about the prevalence, etiology, and patterns of comorbidity in this age group. We investigated the prevalence of BDD symptoms in adolescents and young adults. We also report on the relative importance of genetic and environmental influences on BDD symptoms, and the risk for co-existing psychopathology. Prevalence of BDD symptoms was determined by a validated cut-off on the Dysmorphic Concerns Questionnaire (DCQ) in three population-based twin cohorts at ages 15 (n = 6968), 18 (n = 3738), and 20-28 (n = 4671). Heritability analysis was performed using univariate model-fitting for the DCQ. The risk for co-existing psychopathology was expressed as odds ratios (OR). The prevalence of clinically significant BDD symptoms was estimated to be between 1 and 2% in the different cohorts, with a significantly higher prevalence in females (1.3-3.3%) than in males (0.2-0.6%). The heritability of body dysmorphic concerns was estimated to be 49% (95% CI 38-54%) at age 15, 39% (95% CI 30-46) at age 18, and 37% (95% CI 29-42) at ages 20-28, with the remaining variance being due to non-shared environment. ORs for co-existing neuropsychiatric and alcohol-related problems ranged from 2.3 to 13.2. Clinically significant BDD symptoms are relatively common in adolescence and young adulthood, particularly in females. The low occurrence of BDD symptoms in adolescent boys may indicate sex differences in age of onset and/or etiological mechanisms. BDD symptoms are moderately heritable in young people and associated with an increased risk for co-existing neuropsychiatric and alcohol-related problems.

Treatment of Missing Data in Workforce Education Research

ERIC Educational Resources Information Center

Gemici, Sinan; Rojewski, Jay W.; Lee, In Heok

2012-01-01

Most quantitative analyses in workforce education are affected by missing data. Traditional approaches to remedy missing data problems often result in reduced statistical power and biased parameter estimates due to systematic differences between missing and observed values. This article examines the treatment of missing data in pertinent…

Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.

PubMed

Okou, David T; Mondal, Kajari; Faubion, William A; Kobrynski, Lisa J; Denson, Lee A; Mulle, Jennifer G; Ramachandran, Dhanya; Xiong, Yuning; Svingen, Phyllis; Patel, Viren; Bose, Promita; Waters, Jon P; Prahalad, Sampath; Cutler, David J; Zwick, Michael E; Kugathasan, Subra

2014-05-01

Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD. WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay. We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-to-glycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD. Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.

Describing the genetic architecture of epilepsy through heritability analysis.

PubMed

Speed, Doug; O'Brien, Terence J; Palotie, Aarno; Shkura, Kirill; Marson, Anthony G; Balding, David J; Johnson, Michael R

2014-10-01

Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

ATHENA: A knowledge-based hybrid backpropagation-grammatical evolution neural network algorithm for discovering epistasis among quantitative trait Loci

PubMed Central

2010-01-01

Background Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last decade, yet little heritability in highly studied complex traits has been explained by genetic variation. Non-additive gene-gene interactions, which are not often explored, are thought to be one source of this "missing" heritability. Methods Stochastic methods employing evolutionary algorithms have demonstrated promise in being able to detect and model gene-gene and gene-environment interactions that influence human traits. Here we demonstrate modifications to a neural network algorithm in ATHENA (the Analysis Tool for Heritable and Environmental Network Associations) resulting in clear performance improvements for discovering gene-gene interactions that influence human traits. We employed an alternative tree-based crossover, backpropagation for locally fitting neural network weights, and incorporation of domain knowledge obtainable from publicly accessible biological databases for initializing the search for gene-gene interactions. We tested these modifications in silico using simulated datasets. Results We show that the alternative tree-based crossover modification resulted in a modest increase in the sensitivity of the ATHENA algorithm for discovering gene-gene interactions. The performance increase was highly statistically significant when backpropagation was used to locally fit NN weights. We also demonstrate that using domain knowledge to initialize the search for gene-gene interactions results in a large performance increase, especially when the search space is larger than the search coverage. Conclusions We show that a hybrid optimization procedure, alternative crossover strategies, and incorporation of domain knowledge from publicly available biological databases can result in marked increases in sensitivity and performance of the ATHENA algorithm for detecting and modelling gene-gene interactions that influence a complex human trait. PMID:20875103

DNA Variations in Oculocutaneous Albinism: An Updated Mutation List and Current Outstanding Issues in Molecular Diagnostics

PubMed Central

Simeonov, Dimitre R.; Wang, Xinjing; Wang, Chen; Sergeev, Yuri; Dolinska, Monika; Bower, Matthew; Fischer, Roxanne; Winer, David; Dubrovsky, Genia; Balog, Joan Z.; Huizing, Marjan; Hart, Rachel; Zein, Wadih M.; Gahl, William A.; Brooks, Brian P.; Adams, David R.

2014-01-01

Oculocutaneous albinism (OCA) is a rare genetic disorder of melanin synthesis that results in hypopigmented hair, skin, and eyes. There are four types of OCA, caused by mutations in TYR (OCA-1), OCA2 (OCA-2), TYRP1 (OCA-3), or SLC45A2 (OCA-4). Here we report 22 novel mutations; 14 from a cohort of 61 patients seen as part of the NIH OCA Natural History Study and 8 from a prior study at the University of Minnesota. We also include a comprehensive list of almost 600 previously reported OCA mutations, along with ethnicity information, carrier frequencies, and in silico pathogenicity predictions. In addition to discussing the clinical and molecular features of OCA, we address the cases of apparent missing heritability. In our cohort, 25% of patients did not have two mutations in a single OCA gene. We demonstrate the utility of multiple detection methods to reveal mutations missed by Sanger sequencing. Finally, we review the TYR p.R402Q temperature sensitive variant and confirm its association with cases of albinism with only one identifiable TYR mutation. PMID:23504663

The influence of heritability, neuroticism, maternal warmth and media use on disordered eating behaviors: a prospective analysis of twins.

PubMed

Ferguson, Christopher J; Muñoz, Monica E; Winegard, Ben; Winegard, Bo

2012-09-01

The relative impact of genetic and social influences on disordered eating behaviors (DEB) including binging, purging, excessive dieting and negative self-evaluations about weight remain an issue of debate. The current study sought to examine the relative influence of genetic and social influences on DEB. A 7-year prospective analysis of 580 monozygotic (MZ) and dizygotic (DZ) twins was conducted. Estimates of heritability of DEB were obtained using the DF Analysis Model. Regression equations revealed the relative predictive value of sibling's DEB, neurotic personality, maternal warmth and television and video game exposure on DEB. Heritability estimates for DEB were 0.40 for females and 0.48 for males. Among MZ and DZ twin pairs, female sex, neurotic personality and a genetic variable component, but not maternal warmth or school related problems, predicted DEB. Contrary to the expectations of media effects theory, greater media use was associated with lower DEB among DZ twins and had no influence on MZ twins. These results indicate that DEB is highly heritable and that personality variables may play an important role in the formation of DEB. This suggests that it is important to control for genetic variables when analyzing risk factors for DEB.

PERCH: A Unified Framework for Disease Gene Prioritization.

PubMed

Feng, Bing-Jian

2017-03-01

To interpret genetic variants discovered from next-generation sequencing, integration of heterogeneous information is vital for success. This article describes a framework named PERCH (Polymorphism Evaluation, Ranking, and Classification for a Heritable trait), available at http://BJFengLab.org/. It can prioritize disease genes by quantitatively unifying a new deleteriousness measure called BayesDel, an improved assessment of the biological relevance of genes to the disease, a modified linkage analysis, a novel rare-variant association test, and a converted variant call quality score. It supports data that contain various combinations of extended pedigrees, trios, and case-controls, and allows for a reduced penetrance, an elevated phenocopy rate, liability classes, and covariates. BayesDel is more accurate than PolyPhen2, SIFT, FATHMM, LRT, Mutation Taster, Mutation Assessor, PhyloP, GERP++, SiPhy, CADD, MetaLR, and MetaSVM. The overall approach is faster and more powerful than the existing quantitative method pVAAST, as shown by the simulations of challenging situations in finding the missing heritability of a complex disease. This framework can also classify variants of unknown significance (variants of uncertain significance) by quantitatively integrating allele frequencies, deleteriousness, association, and co-segregation. PERCH is a versatile tool for gene prioritization in gene discovery research and variant classification in clinical genetic testing. © 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Differential methylation is associated with non-syndromic cleft lip and palate and contributes to penetrance effects.

PubMed

Alvizi, Lucas; Ke, Xiayi; Brito, Luciano Abreu; Seselgyte, Rimante; Moore, Gudrun E; Stanier, Philip; Passos-Bueno, Maria Rita

2017-05-26

Non-syndromic cleft lip and/or palate (NSCLP) is a common congenital malformation with a multifactorial model of inheritance. Although several at-risk alleles have been identified, they do not completely explain the high heritability. We postulate that epigenetic factors as DNA methylation might contribute to this missing heritability. Using a Methylome-wide association study in a Brazilian cohort (67 NSCLP, 59 controls), we found 578 methylation variable positions (MVPs) that were significantly associated with NSCLP. MVPs were enriched in regulatory and active regions of the genome and in pathways already implicated in craniofacial development. In an independent UK cohort (171 NSCLP, 177 controls), we replicated 4 out of 11 tested MVPs. We demonstrated a significant positive correlation between blood and lip tissue DNA methylation, indicating blood as a suitable tissue for NSCLP methylation studies. Next, we quantified CDH1 promoter methylation levels in CDH1 mutation-positive families, including penetrants, non-penetrants or non-carriers for NSCLP. We found methylation levels to be significantly higher in the penetrant individuals. Taken together, our results demonstrated the association of methylation at specific genomic locations as contributing factors to both non-familial and familial NSCLP and altered DNA methylation may be a second hit contributing to penetrance.

Remedial Sheets for Progress Checks, Segments 19-40.

ERIC Educational Resources Information Center

New York Inst. of Tech., Old Westbury.

The second part of the Self-Paced Physics Course remediation materials is presented for U. S. Naval Academy students who miss core problems on the progress check. The total of 101 problems is incorporated in this volume to match study segments 19 through 40. Each remedial sheet is composed of a statement of the missed problem and references to…

A CLINICIAN'S GUIDE TO X-LINKED HYPOPHOSPHATEMIA

PubMed Central

Carpenter, Thomas O.; Imel, Erik A.; Holm, Ingrid A.; Jan de Beur, Suzanne M.; Insogna, Karl L.

2011-01-01

X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and XLH support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the “Advances in Rare Bone Diseases Scientific Conference,” held at the National Institutes of Health in October 2008. We briefly review the clinical and pathophysiologic features of the disorder, and offer this guide in response to the conference recommendation, base on our collective accumulated experience in the management of this complex disorder. PMID:21538511

Programming of Essential Hypertension: What Pediatric Cardiologists Need to Know.

PubMed

Morgado, Joana; Sanches, Bruno; Anjos, Rui; Coelho, Constança

2015-10-01

Hypertension is recognized as one of the major contributing factors to cardiovascular disease, but its etiology remains incompletely understood. Known genetic and environmental influences can only explain a small part of the variability in cardiovascular disease risk. The missing heritability is currently one of the most important challenges in blood pressure and hypertension genetics. Recently, some promising approaches have emerged that move beyond the DNA sequence and focus on identification of blood pressure genes regulated by epigenetic mechanisms such as DNA methylation, histone modification and microRNAs. This review summarizes information on gene-environmental interactions that lead toward the developmental programming of hypertension with specific reference to epigenetics and provides pediatricians and pediatric cardiologists with a more complete understanding of its pathogenesis.

Crying without a cause and being easily upset in two-year-olds: heritability and predictive power of behavioral problems.

PubMed

Groen-Blokhuis, Maria M; Middeldorp, Christel M; M van Beijsterveldt, Catharina E; Boomsma, Dorret I

2011-10-01

In order to estimate the influence of genetic and environmental factors on 'crying without a cause' and 'being easily upset' in 2-year-old children, a large twin study was carried out. Prospective data were available for ~18,000 2-year-old twin pairs from the Netherlands Twin Register. A bivariate genetic analysis was performed using structural equation modeling in the Mx software package. The influence of maternal personality characteristics and demographic and lifestyle factors was tested to identify specific risk factors that may underlie the shared environment of twins. Furthermore, it was tested whether crying without a cause and being easily upset were predictive of later internalizing, externalizing and attention problems. Crying without a cause yielded a heritability estimate of 60% in boys and girls. For easily upset, the heritability was estimated at 43% in boys and 31% in girls. The variance explained by shared environment varied between 35% and 63%. The correlation between crying without a cause and easily upset (r = .36) was explained both by genetic and shared environmental factors. Birth cohort, gestational age, socioeconomic status, parental age, parental smoking behavior and alcohol use during pregnancy did not explain the shared environmental component. Neuroticism of the mother explained a small proportion of the additive genetic, but not of the shared environmental effects for easily upset. Crying without a cause and being easily upset at age 2 were predictive of internalizing, externalizing and attention problems at age 7, with effect sizes of .28-.42. A large influence of shared environmental factors on crying without a cause and easily upset was detected. Although these effects could be specific to these items, we could not explain them by personality characteristics of the mother or by demographic and lifestyle factors, and we recognize that these effects may reflect other maternal characteristics. A substantial influence of genetic factors was found for the two items, which are predictive of later behavioral problems.

Chaotic Homes and Children’s Disruptive Behavior

PubMed Central

Jaffee, Sara R.; Haworth, Claire M. A.; Davis, Oliver S. P.; Plomin, Robert

2012-01-01

Chaotic home lives are correlated with behavior problems in children. In the study reported here, we tested whether there was a cross-lagged relation between children’s experience of chaos and their disruptive behaviors (conduct problems and hyperactivity-inattention). Using genetically informative models, we then tested for the first time whether the influence of household chaos on disruptive behavior was environmentally mediated and whether genetic influences on children’s disruptive behaviors accounted for the heritability of household chaos. We measured children’s perceptions of household chaos and parents’ ratings of children’s disruptive behavior at ages 9 and 12 in a sample of 6,286 twin pairs from the Twins Early Development Study (TEDS). There was a phenotypic cross-lagged relation between children’s experiences of household chaos and their disruptive behavior. In genetically informative models, we found that the effect of household chaos on subsequent disruptive behavior was environmentally mediated. However, genetic influences on disruptive behavior did not explain why household chaos was heritable. PMID:22547656

Silver Alerts and the Problem of Missing Adults with Dementia

ERIC Educational Resources Information Center

Carr, Dawn; Muschert, Glenn W.; Kinney, Jennifer; Robbins, Emily; Petonito, Gina; Manning, Lydia; Brown, J. Scott

2010-01-01

In the months following the introduction of the National AMBER (America's Missing: Broadcast Emergency Response) Alert plan used to locate missing and abducted children, Silver Alert programs began to emerge. These programs use the same infrastructure and approach to find a different missing population, cognitively impaired older adults. By late…

A Cautious Note on Auxiliary Variables That Can Increase Bias in Missing Data Problems.

PubMed

Thoemmes, Felix; Rose, Norman

2014-01-01

The treatment of missing data in the social sciences has changed tremendously during the last decade. Modern missing data techniques such as multiple imputation and full-information maximum likelihood are used much more frequently. These methods assume that data are missing at random. One very common approach to increase the likelihood that missing at random is achieved consists of including many covariates as so-called auxiliary variables. These variables are either included based on data considerations or in an inclusive fashion; that is, taking all available auxiliary variables. In this article, we point out that there are some instances in which auxiliary variables exhibit the surprising property of increasing bias in missing data problems. In a series of focused simulation studies, we highlight some situations in which this type of biasing behavior can occur. We briefly discuss possible ways how one can avoid selecting bias-inducing covariates as auxiliary variables.

Multiple Imputation for Multivariate Missing-Data Problems: A Data Analyst's Perspective.

ERIC Educational Resources Information Center

Schafer, Joseph L.; Olsen, Maren K.

1998-01-01

The key ideas of multiple imputation for multivariate missing data problems are reviewed. Software programs available for this analysis are described, and their use is illustrated with data from the Adolescent Alcohol Prevention Trial (W. Hansen and J. Graham, 1991). (SLD)

A Review On Missing Value Estimation Using Imputation Algorithm

NASA Astrophysics Data System (ADS)

Armina, Roslan; Zain, Azlan Mohd; Azizah Ali, Nor; Sallehuddin, Roselina

2017-09-01

The presence of the missing value in the data set has always been a major problem for precise prediction. The method for imputing missing value needs to minimize the effect of incomplete data sets for the prediction model. Many algorithms have been proposed for countermeasure of missing value problem. In this review, we provide a comprehensive analysis of existing imputation algorithm, focusing on the technique used and the implementation of global or local information of data sets for missing value estimation. In addition validation method for imputation result and way to measure the performance of imputation algorithm also described. The objective of this review is to highlight possible improvement on existing method and it is hoped that this review gives reader better understanding of imputation method trend.

Nature and Nurture Strike (Out) Again.

ERIC Educational Resources Information Center

Scarr, Sandra; Weinberg, Richard A.

1979-01-01

A reply to Plomin's critique and some criticisms of Munsinger's review of adopted child literature are presented. Selective bias in adoptee samples, implicit assumptions in models that lead to heritability estimates, and problems produced by lack of an accepted model of environmental transmission are also discussed. (Author/RD)

A Review of Missing Data Handling Methods in Education Research

ERIC Educational Resources Information Center

Cheema, Jehanzeb R.

2014-01-01

Missing data are a common occurrence in survey-based research studies in education, and the way missing values are handled can significantly affect the results of analyses based on such data. Despite known problems with performance of some missing data handling methods, such as mean imputation, many researchers in education continue to use those…

Effects of Modified Schema-Based Instruction on Real-World Algebra Problem Solving of Students with Autism Spectrum Disorder and Moderate Intellectual Disability

ERIC Educational Resources Information Center

Root, Jenny Rose

2016-01-01

The current study evaluated the effects of modified schema-based instruction (SBI) on the algebra problem solving skills of three middle school students with autism spectrum disorder and moderate intellectual disability (ASD/ID). Participants learned to solve two types of group word problems: missing-whole and missing-part. The themes of the word…

Genetics of Nicotine Dependence and Pharmacotherapy

PubMed Central

Lessov-Schlaggar, Christina N.; Pergadia, Michele L.; Khroyan, Taline V.; Swan, Gary E.

2008-01-01

Nicotine dependence is substantially heritable. Several regions across the genome have been implicated in containing genes that confer liability to nicotine dependence and variation in individual genes has been associated with nicotine dependence. Smoking cessation measures are also heritable, and measured genetic variation is associated with nicotine dependence treatment efficacy. Despite significant strides in the understanding of the relative contribution of genetic and environmental factors to nicotine dependence and treatment, emergent challenges necessitate interdisciplinary coordinated effort for effective problem solving. These challenges include refinement of the nicotine dependence phenotype, better understanding of the dynamic interplay between genes and environment in nicotine dependence etiology, application and development of molecular and statistical methodology that can adequately address vast amounts of data, and continuous translational cross-talk. PMID:17888884

Heritability Analyses of IQ Scores: Science or Numerology?

ERIC Educational Resources Information Center

Layzer, David

1974-01-01

Examines limitations of the heritability concept and heritability analysis, and discusses a conventional application of heritability analysis, IQ scores as measurements of a phenotypic character, the heritability of IQ, and the relationship of IQ and race. (JR)

The Missing Curriculum in Physics Problem-Solving Education

NASA Astrophysics Data System (ADS)

Williams, Mobolaji

2018-05-01

Physics is often seen as an excellent introduction to science because it allows students to learn not only the laws governing the world around them, but also, through the problems students solve, a way of thinking which is conducive to solving problems outside of physics and even outside of science. In this article, we contest this latter idea and argue that in physics classes, students do not learn widely applicable problem-solving skills because physics education almost exclusively requires students to solve well-defined problems rather than the less-defined problems which better model problem solving outside of a formal class. Using personal, constructed, and the historical accounts of Schrödinger's development of the wave equation and Feynman's development of path integrals, we argue that what is missing in problem-solving education is practice in identifying gaps in knowledge and in framing these knowledge gaps as questions of the kind answerable using techniques students have learned. We discuss why these elements are typically not taught as part of the problem-solving curriculum and end with suggestions on how to incorporate these missing elements into physics classes.

Genome-Wide Association Study of the Child Behavior Checklist Dysregulation Profile

ERIC Educational Resources Information Center

Mick, Eric; McGough, James; Loo, Sandra; Doyle, Alysa E.; Wozniak, Janet; Wilens, Timothy E.; Smalley, Susan; McCracken, James; Biederman, Joseph; Faraone, Stephen V.

2011-01-01

Objective: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for…

Suspended Education in Massachusetts: Using Days of Lost Instruction Due to Suspension to Evaluate Our Schools

ERIC Educational Resources Information Center

Losen, Daniel J.; Sun, Wei-Ling; Keith, Michael A., II

2017-01-01

Missed instruction can have a devastating impact on educational outcomes. Some reasons for missed instruction are beyond the control of schools and districts: some students miss school due to mental or physical illness or injury, and transportation problems sometimes are to blame. One major reason for missed instruction that schools can directly…

Genetics of diabetes--are we missing the genes or the disease?

PubMed

Groop, Leif; Pociot, Flemming

2014-01-25

Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of different organs, especially the eyes, kidneys, nerves, heart, and blood vessels. Several pathogenic processes are involved in the development of diabetes. These range from autoimmune destruction of the beta-cells of the pancreas with consequent insulin deficiency to abnormalities that result in resistance to insulin action (American Diabetes Association, 2011). The vast majority of cases of diabetes fall into two broad categories. In type 1 diabetes (T1D), the cause is an absolute deficiency of insulin secretion, whereas in type 2 diabetes (T2D), the cause is a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. However, the subdivision into two main categories represents a simplification of the real situation, and research during the recent years has shown that the disease is much more heterogeneous than a simple subdivision into two major subtypes assumes. Worldwide prevalence figures estimate that there are 280 million diabetic patients in 2011 and more than 500 million in 2030 (http://www.diabetesatlas.org/). In Europe, about 6-8% of the population suffer from diabetes, of them about 90% has T2D and 10% T1D, thereby making T2D to the fastest increasing disease in Europe and worldwide. This epidemic has been ascribed to a collision between the genes and the environment. While our knowledge about the genes is clearly better for T1D than for T2D given the strong contribution of variation in the HLA region to the risk of T1D, the opposite is the case for T2D, where our knowledge about the environmental triggers (obesity, lack of exercise) is much better than the understanding of the underlying genetic causes. This lack of knowledge about the underlying genetic causes of diabetes is often referred to as missing heritability (Manolio et al., 2009) which exceeds 80% for T2D but less than 25% for T1D. In the following review, we will discuss potential sources of this missing heritability which also includes the possibility that our definition of diabetes and its subgroups is imprecise and thereby making the identification of genetic causes difficult. Copyright © 2013. Published by Elsevier Ireland Ltd.

Implications for the missing low-mass galaxies (satellites) problem from cosmic shear

NASA Astrophysics Data System (ADS)

Jimenez, Raul; Verde, Licia; Kitching, Thomas D.

2018-06-01

The number of observed dwarf galaxies, with dark matter mass ≲ 1011 M⊙ in the Milky Way or the Andromeda galaxy does not agree with predictions from the successful ΛCDM paradigm. To alleviate this problem a suppression of dark matter clustering power on very small scales has been conjectured. However, the abundance of dark matter halos outside our immediate neighbourhood (the Local Group) seem to agree with the ΛCDM-expected abundance. Here we connect these problems to observations of weak lensing cosmic shear, pointing out that cosmic shear can make significant statements about the missing satellites problem in a statistical way. As an example and pedagogical application we use recent constraints on small-scales power suppression from measurements of the CFHTLenS data. We find that, on average, in a region of ˜Gpc3 there is no significant small-scale power suppression. This implies that suppression of small-scale power is not a viable solution to the `missing satellites problem' or, alternatively, that on average in this volume there is no `missing satellites problem' for dark matter masses ≳ 5 × 109 M⊙. Further analysis of current and future weak lensing surveys will probe much smaller scales, k > 10h Mpc-1 corresponding roughly to masses M < 109M⊙.

The continuing problem of missed test results in an integrated health system with an advanced electronic medical record.

PubMed

Wahls, Terry; Haugen, Thomas; Cram, Peter

2007-08-01

Missed results can cause needless treatment delays. However, there is little data about the magnitude of this problem and the systems that clinics use to manage test results. Surveys about potential problems related to test results management were developed and administered to clinical staff in a regional Veterans Administration (VA) health care network. The provider survey, conducted four times between May 2005 and October 2006, sampling VA staff physicians, physician assistants, nurse practitioners, and internal medicine trainees, asked questions about the frequency of missed results and diagnosis or treatment delays seen in the antecedent two weeks in their clinics, or if a trainee, the antecedent month. Clinical staff survey response rate was 39% (143 of 370), with 40% using standard operating procedures to manage test results. Forty-four percent routinely reported all results to patients. The provider survey response rate was 50% (441 of 884) overall, with responses often (37% overall; range 29% to 46%) indicating they had seen patients with diagnosis or treatment delays attributed to a missed result; 15% reported two or more such encounters. Even in an integrated health system with an advanced electronic medical record, missed test results and associated diagnosis or treatment delays are common. Additional study and measures of missed results and associated treatment delays are needed.

An assessment of the reliability of quantitative genetics estimates in study systems with high rate of extra-pair reproduction and low recruitment.

PubMed

Bourret, A; Garant, D

2017-03-01

Quantitative genetics approaches, and particularly animal models, are widely used to assess the genetic (co)variance of key fitness related traits and infer adaptive potential of wild populations. Despite the importance of precision and accuracy of genetic variance estimates and their potential sensitivity to various ecological and population specific factors, their reliability is rarely tested explicitly. Here, we used simulations and empirical data collected from an 11-year study on tree swallow (Tachycineta bicolor), a species showing a high rate of extra-pair paternity and a low recruitment rate, to assess the importance of identity errors, structure and size of the pedigree on quantitative genetic estimates in our dataset. Our simulations revealed an important lack of precision in heritability and genetic-correlation estimates for most traits, a low power to detect significant effects and important identifiability problems. We also observed a large bias in heritability estimates when using the social pedigree instead of the genetic one (deflated heritabilities) or when not accounting for an important cause of resemblance among individuals (for example, permanent environment or brood effect) in model parameterizations for some traits (inflated heritabilities). We discuss the causes underlying the low reliability observed here and why they are also likely to occur in other study systems. Altogether, our results re-emphasize the difficulties of generalizing quantitative genetic estimates reliably from one study system to another and the importance of reporting simulation analyses to evaluate these important issues.

Heritability of body weight and resistance to ammonia in the Pacific white shrimp Litopenaeus vannamei juveniles

NASA Astrophysics Data System (ADS)

Li, Wenjia; Lu, Xia; Luan, Sheng; Luo, Kun; Sui, Juan; Kong, Jie

2016-09-01

Ammonia, toxic to aquaculture organisms, represents a potential problem in aquaculture systems, and the situation is exacerbated in closed and intensive shrimp farming operations, expecially for Litopenaeus vannamei. Assessing the potential for the genetic improvement of resistance to ammonia in L. vannamei requires knowledge of the genetic parameters of this trait. The heritability of resistance to ammonia was estimated using two descriptors in the present study: the survival time (ST) and the survival status at half lethal time (SS50) for each individual under high ammonia challenge. The heritability of ST and SS50 were low (0.154 4±0.044 6 and 0.147 5±0.040 0, respectively), but they were both significantly different from zero ( P<0.01). Moreover, these two estimates were basically the same and showed no significant differences from each other ( P>0.05), suggesting that ST and SS50 could be used as suitable indicators for resistance to ammonia. There were also positive phenotypic and genetic correlation between resistance to ammonia and body weight, which means that resistance to ammonia can be enhanced by the improvement of husbandry practices that increase the body weight. The results from the present study suggest that the selection for higher body weight does not have any negative consequences for resistance to ammonia. In addition to quantitative genetics, tools from molecular genetics can be applied to selective breeding programs to improve the efficiency of selection for traits with low heritability.

Methods for Handling Missing Secondary Respondent Data

ERIC Educational Resources Information Center

Young, Rebekah; Johnson, David

2013-01-01

Secondary respondent data are underutilized because researchers avoid using these data in the presence of substantial missing data. The authors reviewed, evaluated, and tested solutions to this problem. Five strategies of dealing with missing partner data were reviewed: (a) complete case analysis, (b) inverse probability weighting, (c) correction…

Why Missing Data Matter in the Longitudinal Study of Adolescent Development: Using the 4-H Study to Understand the Uses of Different Missing Data Methods

ERIC Educational Resources Information Center

Jelicic, Helena; Phelps, Erin; Lerner, Richard M.

2010-01-01

The study of adolescent development rests on methodologically appropriate collection and interpretation of longitudinal data. While all longitudinal studies of adolescent development involve missing data, the methods to treat missingness that have been recommended most often focus on missing data from cross-sectional studies. The problems of…

Human-directed social behaviour in dogs shows significant heritability.

PubMed

Persson, M E; Roth, L S V; Johnsson, M; Wright, D; Jensen, P

2015-04-01

Through domestication and co-evolution with humans, dogs have developed abilities to attract human attention, e.g. in a manner of seeking assistance when faced with a problem solving task. The aims of this study were to investigate within breed variation in human-directed contact seeking in dogs and to estimate its genetic basis. To do this, 498 research beagles, bred and kept under standardized conditions, were tested in an unsolvable problem task. Contact seeking behaviours recorded included both eye contact and physical interactions. Behavioural data was summarized through a principal component analysis, resulting in four components: test interactions, social interactions, eye contact and physical contact. Females scored significantly higher on social interactions and physical contact and age had an effect on eye contact scores. Narrow sense heritabilities (h(2) ) of the two largest components were estimated at 0.32 and 0.23 but were not significant for the last two components. These results show that within the studied dog population, behavioural variation in human-directed social behaviours was sex dependent and that the utilization of eye contact seeking increased with age and experience. Hence, heritability estimates indicate a significant genetic contribution to the variation found in human-directed social interactions, suggesting that social skills in dogs have a genetic basis, but can also be shaped and enhanced through individual experiences. This research gives the opportunity to further investigate the genetics behind dogs' social skills, which could also play a significant part into research on human social disorders such as autism. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

A Comparison of Missing-Data Procedures for Arima Time-Series Analysis

ERIC Educational Resources Information Center

Velicer, Wayne F.; Colby, Suzanne M.

2005-01-01

Missing data are a common practical problem for longitudinal designs. Time-series analysis is a longitudinal method that involves a large number of observations on a single unit. Four different missing-data methods (deletion, mean substitution, mean of adjacent observations, and maximum likelihood estimation) were evaluated. Computer-generated…

They Remember the "Lost" People.

ERIC Educational Resources Information Center

Klages, Karen

Estimates of the number of children currently missing in the United States are only approximate because there is no effective central data bank to collect information on missing persons and unidentified bodies. However, the problem appears to have reached epidemic proportions. Some parents of missing persons have formed organizations in different…

The Empirical Nature and Statistical Treatment of Missing Data

ERIC Educational Resources Information Center

Tannenbaum, Christyn E.

2009-01-01

Introduction. Missing data is a common problem in research and can produce severely misleading analyses, including biased estimates of statistical parameters, and erroneous conclusions. In its 1999 report, the APA Task Force on Statistical Inference encouraged authors to report complications such as missing data and discouraged the use of…

Parental Divorce and Adolescent Delinquency: Ruling out the Impact of Common Genes

ERIC Educational Resources Information Center

Burt, S. Alexandra; Barnes, Ashlee R.; McGue, Matt; Iacono, William G.

2008-01-01

Although the well-documented association between parental divorce and adolescent delinquency is generally assumed to be environmental (i.e., causal) in origin, genetic mediation is also possible. Namely, the behavior problems often found in children of divorce could derive from similar pathology in the parents, pathology that is both heritable and…

Severe Affective and Behavioural Dysregulation Is Associated with Significant Psychosocial Adversity and Impairment

ERIC Educational Resources Information Center

Jucksch, Viola; Salbach-Andrae, Harriet; Lenz, Klaus; Goth, Kirstin; Dopfner, Manfred; Poustka, Fritz; Freitag, Christine M.; Lehmkuhl, Gerd; Lehmkuhl, Ulrike; Holtmann, Martin

2011-01-01

Background: Recently, a highly heritable behavioral phenotype of simultaneous deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales has been identified on the Child Behavior Checklist (CBCL-Dysregulation Profile, CBCL-DP). This study aims to investigate psychosocial adversity and impairment of the CBCL-DP.…

Heritability of personality disorder traits: a twin study.

PubMed

Jang, K L; Livesley, W J; Vernon, P A; Jackson, D N

1996-12-01

Genetic and non-genetic influences on the hierarchy of traits that delineate personality disorder as measured by the Dimensional Assessment of Personality Problems (DAPP-DQ) scale were examined using data from a sample of 483 volunteer twin pairs (236 monozygotic pairs and 247 dizygotic pairs). The DAPP-DQ assesses four higher-order factors, 18 basic dimensions and 69 facet traits of personality disorder. The correlation coefficients for monozygotic and dizygotic twin pairs ranged from 0.26 to 0.56 and from 0.03 to 0.41, respectively. Broad heritability estimates ranged from 0 to 58% (median value 45%). Additive genetic effects and unique environmental effects emerged as the primary influences on these scales, with unique environmental influences accounting for the largest proportion of the variance for most traits at all levels of the hierarchy.

Genetic and Environmental Influences on Adult Mental Health: Evidence for Gene-Environment Interplay as a Function of Maternal and Paternal Discipline and Affection.

PubMed

South, Susan C; Jarnecke, Amber M

2015-07-01

Researchers have long theorized that genetic influence on mental health may differ as a function of environmental risk factors. One likely moderator of genetic and environmental influences on psychopathological symptoms is parenting behavior, as phenotypic research shows that negative aspects of parent-child relationships are associated with greater likelihood of mental illness in adulthood. The current study examined whether levels of reported parental discipline and affection experienced in childhood act as a trigger, or buffer, for adult mental health problems. Results from a nationwide twin sample suggest level of father's discipline and affection, as reported by now-adult twins, moderated genetic and environmental influences on internalizing symptoms in adulthood, such that heritability was greatest at the highest levels of discipline and affection. Father's affection also moderated the etiological influences on alcohol use problems, with greater heritability at the lowest levels of affection. No moderating effect was found for mothers. Findings suggest relationships with fathers in childhood can have long-lasting effects on the etiological influences on adult mental health outcomes.

Reliability and Validity in Measuring the Value Added of Schools

ERIC Educational Resources Information Center

van de Grift, Wim

2009-01-01

Instability in the school population between school entrance and school leaving is not "just a problem of missing data" but often the visible result of the educational problems in some schools and is, therefore, not merely to be treated as missing data but as indicator for the quality of educational processes. Even the most superior…

A Couple of "Lim (h[right arrow]0)-Is-Missing" Problems

ERIC Educational Resources Information Center

Lau, Ko Hin

2007-01-01

Since most students "hate" the concept of limit, in order to make them "happier," this article suggests a couple of naive "lim (h[right arrow]0)-is-missing" problems for them to try for fun. Indeed, differential functional equations that are related to difference quotients in calculus are studied in this paper. In particular, two interesting…

Addressing the Missing Instructional Data Problem: Using a Teacher Log to Document Tier 1 Instruction

ERIC Educational Resources Information Center

Kurz, Alexander; Elliott, Stephen N.; Roach, Andrew T.

2015-01-01

Response-to-intervention (RTI) systems posit that Tier 1 consists of high-quality general classroom instruction using evidence-based methods to address the needs of most students. However, data on the extent to which general education teachers provide such instruction are rarely collected. This missing instructional data problem may result in RTI…

Detection of gene-environment interaction in pedigree data using genome-wide genotypes.

PubMed

Nivard, Michel G; Middeldorp, Christel M; Lubke, Gitta; Hottenga, Jouke-Jan; Abdellaoui, Abdel; Boomsma, Dorret I; Dolan, Conor V

2016-12-01

Heritability may be estimated using phenotypic data collected in relatives or in distantly related individuals using genome-wide single nucleotide polymorphism (SNP) data. We combined these approaches by re-parameterizing the model proposed by Zaitlen et al and extended this model to include moderation of (total and SNP-based) genetic and environmental variance components by a measured moderator. By means of data simulation, we demonstrated that the type 1 error rates of the proposed test are correct and parameter estimates are accurate. As an application, we considered the moderation by age or year of birth of variance components associated with body mass index (BMI), height, attention problems (AP), and symptoms of anxiety and depression. The genetic variance of BMI was found to increase with age, but the environmental variance displayed a greater increase with age, resulting in a proportional decrease of the heritability of BMI. Environmental variance of height increased with year of birth. The environmental variance of AP increased with age. These results illustrate the assessment of moderation of environmental and genetic effects, when estimating heritability from combined SNP and family data. The assessment of moderation of genetic and environmental variance will enhance our understanding of the genetic architecture of complex traits.

Etiology of Stability and Growth of Internalizing and Externalizing Behavior Problems Across Childhood and Adolescence.

PubMed

Hatoum, Alexander S; Rhee, Soo Hyun; Corley, Robin P; Hewitt, John K; Friedman, Naomi P

2018-04-20

Internalizing and externalizing behaviors are heritable, and show genetic stability during childhood and adolescence. Less work has explored how genes influence individual differences in developmental trajectories. We estimated ACE biometrical latent growth curve models for the Teacher Report Form (TRF) and parent Child Behavior Checklist (CBCL) internalizing and externalizing scales from ages 7 to 16 years in 408 twin pairs from the Colorado Longitudinal Twin Study. We found that Intercept factors were highly heritable for both internalizing and externalizing behaviors (a2 = .61-.92), with small and nonsignificant environmental influences for teacher-rated data but significant nonshared environmental influences for parent-rated data. There was some evidence of heritability of decline in internalizing behavior (Slopes for teacher and parent ratings), but the Slope genetic variance was almost entirely shared with that for the Intercept when different than zero. These results suggest that genetic effects on these developmental trajectories operate primarily on initial levels and stability, with no significant unique genetic influences for change. Finally, cross-rater analyses of the growth factor scores revealed moderate to large genetic and environmental associations between growth factors derived from parents' and teachers' ratings, particularly the Intercepts.

Shared etiology of phonological memory and vocabulary deficits in school-age children.

PubMed

Peterson, Robin L; Pennington, Bruce F; Samuelsson, Stefan; Byrne, Brian; Olson, Richard K

2013-08-01

The goal of this study was to investigate the etiologic basis for the association between deficits in phonological memory (PM) and vocabulary in school-age children. Children with deficits in PM or vocabulary were identified within the International Longitudinal Twin Study (ILTS; Samuelsson et al., 2005). The ILTS includes 1,045 twin pairs (between the ages of 5 and 8 years) from the United States, Australia, and Scandinavia. The authors applied the DeFries-Fulker ( DeFries & Fulker, 1985, 1988) regression method to determine whether problems in PM and vocabulary tend to co-occur because of overlapping genes, overlapping environmental risk factors, or both. Among children with isolated PM deficits, the authors found significant bivariate heritability of PM and vocabulary weaknesses both within and across time. However, when probands were selected for a vocabulary deficit, there was no evidence for bivariate heritability. In this case, it appears that the PM-vocabulary relationship is caused by common shared environmental experiences. The findings are consistent with previous research on the heritability of specific language impairment and suggest that there are etiologic subgroups of children with low vocabulary for different reasons, 1 being more influenced by genes and another being more influenced by environment.

Sparse subspace clustering for data with missing entries and high-rank matrix completion.

PubMed

Fan, Jicong; Chow, Tommy W S

2017-09-01

Many methods have recently been proposed for subspace clustering, but they are often unable to handle incomplete data because of missing entries. Using matrix completion methods to recover missing entries is a common way to solve the problem. Conventional matrix completion methods require that the matrix should be of low-rank intrinsically, but most matrices are of high-rank or even full-rank in practice, especially when the number of subspaces is large. In this paper, a new method called Sparse Representation with Missing Entries and Matrix Completion is proposed to solve the problems of incomplete-data subspace clustering and high-rank matrix completion. The proposed algorithm alternately computes the matrix of sparse representation coefficients and recovers the missing entries of a data matrix. The proposed algorithm recovers missing entries through minimizing the representation coefficients, representation errors, and matrix rank. Thorough experimental study and comparative analysis based on synthetic data and natural images were conducted. The presented results demonstrate that the proposed algorithm is more effective in subspace clustering and matrix completion compared with other existing methods. Copyright © 2017 Elsevier Ltd. All rights reserved.

The genetic basis for the selection of dairy goats with enhanced resistance to gastrointestinal nematodes

PubMed Central

Heckendorn, Felix; Bieber, Anna; Werne, Steffen; Saratsis, Anastasios; Maurer, Veronika; Stricker, Chris

2017-01-01

Gastrointestinal nematodes (GIN) severely affect small ruminant production worldwide. Increasing problems of anthelmintic resistance have given strong impetus to the search for alternative strategies to control GIN. Selection of animals with an enhanced resistance to GIN has been shown to be successful in sheep. In goats, the corresponding information is comparatively poor. Therefore, the present study was designed to provide reliable data on heritabilities of and genetic correlations between phenotypic traits linked to GIN and milk yield in two major dairy goat breeds (Alpine and Saanen). In all, 20 herds totalling 1303 goats were enrolled in the study. All herds had (i) a history of gastrointestinal nematode infection, (ii) uniform GIN exposure on pasture and (iii) regular milk recordings. For all goats, individual recordings of faecal egg counts (FEC), FAMACHA© eye score, packed cell volume (PCV) and milk yield were performed twice a year with an anthelmintic treatment in between. The collected phenotypic data were multivariately modelled using animal as a random effect with its covariance structure inferred from the pedigree, enabling estimation of the heritabilities of the respective traits and the genetic correlation between them. The heritabilities of FEC, FAMACHA© and PCV were 0.07, 0.22 and 0.22, respectively. The genetic correlation between FEC and FAMACHA© was close to zero and −0.41 between FEC and PCV. The phenotypic correlation between FEC and milk yield was close to zero, whereas the genetic correlation was 0.49. Our data suggest low heritability of FEC in Saanen and Alpine goats and an unfavourable genetic correlation of FEC with milk yield. PMID:28792887

Strategies for Dealing with Missing Accelerometer Data.

PubMed

Stephens, Samantha; Beyene, Joseph; Tremblay, Mark S; Faulkner, Guy; Pullnayegum, Eleanor; Feldman, Brian M

2018-05-01

Missing data is a universal research problem that can affect studies examining the relationship between physical activity measured with accelerometers and health outcomes. Statistical techniques are available to deal with missing data; however, available techniques have not been synthesized. A scoping review was conducted to summarize the advantages and disadvantages of identified methods of dealing with missing data from accelerometers. Missing data poses a threat to the validity and interpretation of trials using physical activity data from accelerometry. Imputation using multiple imputation techniques is recommended to deal with missing data and improve the validity and interpretation of studies using accelerometry. Copyright © 2018 Elsevier Inc. All rights reserved.

Do word-problem features differentially affect problem difficulty as a function of students' mathematics difficulty with and without reading difficulty?

PubMed

Powell, Sarah R; Fuchs, Lynn S; Fuchs, Douglas; Cirino, Paul T; Fletcher, Jack M

2009-01-01

This study examined whether and, if so, how word-problem features differentially affect problem difficulty as a function of mathematics difficulty (MD) status: no MD (n = 109), MD only (n = 109), or MD in combination with reading difficulties (MDRD; n = 109). The problem features were problem type (total, difference, or change) and position of missing information in the number sentence representing the word problem (first, second, or third position). Students were assessed on 14 word problems near the beginning of third grade. Consistent with the hypothesis that mathematical cognition differs as a function of MD subtype, problem type affected problem difficulty differentially for MDRD versus MD-only students; however, the position of missing information in word problems did not. Implications for MD subtyping and for instruction are discussed.

Heritability in the genomics era--concepts and misconceptions.

PubMed

Visscher, Peter M; Hill, William G; Wray, Naomi R

2008-04-01

Heritability allows a comparison of the relative importance of genes and environment to the variation of traits within and across populations. The concept of heritability and its definition as an estimable, dimensionless population parameter was introduced by Sewall Wright and Ronald Fisher nearly a century ago. Despite continuous misunderstandings and controversies over its use and application, heritability remains key to the response to selection in evolutionary biology and agriculture, and to the prediction of disease risk in medicine. Recent reports of substantial heritability for gene expression and new estimation methods using marker data highlight the relevance of heritability in the genomics era.

A longitudinal twin study on IQ, executive functioning, and attention problems during childhood and early adolescence.

PubMed

Polderman, Tinca J C; Gosso, M Florencia; Posthuma, Danielle; Van Beijsterveldt, Toos C E M; Heutink, Peter; Verhulst, Frank C; Boomsma, Dorret I

2006-12-01

Variation in human behavior may be caused by differences in genotype and by non-genetic differences ("environment") between individuals. The relative contributions of genotype (G) and environment (E) to phenotypic variation can be assessed with the classical twin design. We illustrate this approach with longitudinal data collected in 5 and 12-year-old Dutch twins. At age 5 data on cognitive abilities as assessed with a standard intelligence test (IQ), working memory, selective and sustained attention, and attention problems were collected in 237 twin pairs. Seven years later, 172 twin pairs participated again when they were 12 years old and underwent a similar protocol. Results showed that variation in all phenotypes was influenced by genetic factors. For IQ the heritability estimates increased from 30% at age 5, to 80% at age 12. For executive functioning performance genetic factors accounted for around 50% of the variance at both ages. Attention problems showed high heritabilities (above 60%) at both ages, for maternal and teacher ratings. Longitudinal analyses revealed that executive functioning during childhood was weakly correlated with IQ scores at age 12. Attention problems during childhood, as rated by the mother and the teacher were stronger predictors (r = -0.28 and -0.36, respectively). This association could be attributed to a partly overlapping set of genes influencing attention problems at age 5 and IQ at age 12. IQ performance at age 5 was the best predictor of IQ at age 12. IQ at both ages was influenced by the same genes, whose influence was amplified during development.

Two methods for parameter estimation using multiple-trait models and beef cattle field data.

PubMed

Bertrand, J K; Kriese, L A

1990-08-01

Two methods are presented for estimating variances and covariances from beef cattle field data using multiple-trait sire models. Both methods require that the first trait have no missing records and that the contemporary groups for the second trait be subsets of the contemporary groups for the first trait; however, the second trait may have missing records. One method uses pseudo expectations involving quadratics composed of the solutions and the right-hand sides of the mixed model equations. The other method is an extension of Henderson's Simple Method to the multiple trait case. Neither of these methods requires any inversions of large matrices in the computation of the parameters; therefore, both methods can handle very large sets of data. Four simulated data sets were generated to evaluate the methods. In general, both methods estimated genetic correlations and heritabilities that were close to the Restricted Maximum Likelihood estimates and the true data set values, even when selection within contemporary groups was practiced. The estimates of residual correlations by both methods, however, were biased by selection. These two methods can be useful in estimating variances and covariances from multiple-trait models in large populations that have undergone a minimal amount of selection within contemporary groups.

A comparison of model-based imputation methods for handling missing predictor values in a linear regression model: A simulation study

NASA Astrophysics Data System (ADS)

Hasan, Haliza; Ahmad, Sanizah; Osman, Balkish Mohd; Sapri, Shamsiah; Othman, Nadirah

2017-08-01

In regression analysis, missing covariate data has been a common problem. Many researchers use ad hoc methods to overcome this problem due to the ease of implementation. However, these methods require assumptions about the data that rarely hold in practice. Model-based methods such as Maximum Likelihood (ML) using the expectation maximization (EM) algorithm and Multiple Imputation (MI) are more promising when dealing with difficulties caused by missing data. Then again, inappropriate methods of missing value imputation can lead to serious bias that severely affects the parameter estimates. The main objective of this study is to provide a better understanding regarding missing data concept that can assist the researcher to select the appropriate missing data imputation methods. A simulation study was performed to assess the effects of different missing data techniques on the performance of a regression model. The covariate data were generated using an underlying multivariate normal distribution and the dependent variable was generated as a combination of explanatory variables. Missing values in covariate were simulated using a mechanism called missing at random (MAR). Four levels of missingness (10%, 20%, 30% and 40%) were imposed. ML and MI techniques available within SAS software were investigated. A linear regression analysis was fitted and the model performance measures; MSE, and R-Squared were obtained. Results of the analysis showed that MI is superior in handling missing data with highest R-Squared and lowest MSE when percent of missingness is less than 30%. Both methods are unable to handle larger than 30% level of missingness.

Missing Data and Multiple Imputation in the Context of Multivariate Analysis of Variance

ERIC Educational Resources Information Center

Finch, W. Holmes

2016-01-01

Multivariate analysis of variance (MANOVA) is widely used in educational research to compare means on multiple dependent variables across groups. Researchers faced with the problem of missing data often use multiple imputation of values in place of the missing observations. This study compares the performance of 2 methods for combining p values in…

SPSS Syntax for Missing Value Imputation in Test and Questionnaire Data

ERIC Educational Resources Information Center

van Ginkel, Joost R.; van der Ark, L. Andries

2005-01-01

A well-known problem in the analysis of test and questionnaire data is that some item scores may be missing. Advanced methods for the imputation of missing data are available, such as multiple imputation under the multivariate normal model and imputation under the saturated logistic model (Schafer, 1997). Accompanying software was made available…

Genetics Home Reference: Fraser syndrome

MedlinePlus

... them, or they may be small ( microphthalmia ) or missing (anophthalmia). Eye abnormalities typically lead to impairment or ... other problems related to abnormal eye development, including missing eyebrows or eyelashes or a patch of hair ...

The "Missing Males" and Other Gender-Related Issues in Music Education: A Critical Analysis of Evidence from the Music Supervisors' Journal, 1914-1924.

ERIC Educational Resources Information Center

Koza, Julia Eklund

Boys' reluctance to participate in music education programs, particularly in school singing groups -- termed in this paper the "missing males" problem -- is just one among many pressing gender problems in music education. In order to discover whether boys' lack of participation in music, along with other gender-related issues, are merely…

Multi-task Gaussian process for imputing missing data in multi-trait and multi-environment trials.

PubMed

Hori, Tomoaki; Montcho, David; Agbangla, Clement; Ebana, Kaworu; Futakuchi, Koichi; Iwata, Hiroyoshi

2016-11-01

A method based on a multi-task Gaussian process using self-measuring similarity gave increased accuracy for imputing missing phenotypic data in multi-trait and multi-environment trials. Multi-environmental trial (MET) data often encounter the problem of missing data. Accurate imputation of missing data makes subsequent analysis more effective and the results easier to understand. Moreover, accurate imputation may help to reduce the cost of phenotyping for thinned-out lines tested in METs. METs are generally performed for multiple traits that are correlated to each other. Correlation among traits can be useful information for imputation, but single-trait-based methods cannot utilize information shared by traits that are correlated. In this paper, we propose imputation methods based on a multi-task Gaussian process (MTGP) using self-measuring similarity kernels reflecting relationships among traits, genotypes, and environments. This framework allows us to use genetic correlation among multi-trait multi-environment data and also to combine MET data and marker genotype data. We compared the accuracy of three MTGP methods and iterative regularized PCA using rice MET data. Two scenarios for the generation of missing data at various missing rates were considered. The MTGP performed a better imputation accuracy than regularized PCA, especially at high missing rates. Under the 'uniform' scenario, in which missing data arise randomly, inclusion of marker genotype data in the imputation increased the imputation accuracy at high missing rates. Under the 'fiber' scenario, in which missing data arise in all traits for some combinations between genotypes and environments, the inclusion of marker genotype data decreased the imputation accuracy for most traits while increasing the accuracy in a few traits remarkably. The proposed methods will be useful for solving the missing data problem in MET data.

Comparison of the Heritability of Schizophrenia and Endophenotypes in the COGS-1 Family Study

PubMed Central

Light, Gregory; Greenwood, Tiffany A.; Swerdlow, Neal R.; Calkins, Monica E.; Freedman, Robert; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Sprock, Joyce; Stone, William S.; Sugar, Catherine A.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Braff, David L.

2014-01-01

Background: Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a “heritability gap” between the diagnosis and related endophenotypes. Methods: Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families. Results: The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively. Conclusions: Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis. PMID:24903414

Comparison of the heritability of schizophrenia and endophenotypes in the COGS-1 family study.

PubMed

Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L

2014-11-01

Twin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes. Nuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families. The heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively. Endophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2014.

A MAP-based image interpolation method via Viterbi decoding of Markov chains of interpolation functions.

PubMed

Vedadi, Farhang; Shirani, Shahram

2014-01-01

A new method of image resolution up-conversion (image interpolation) based on maximum a posteriori sequence estimation is proposed. Instead of making a hard decision about the value of each missing pixel, we estimate the missing pixels in groups. At each missing pixel of the high resolution (HR) image, we consider an ensemble of candidate interpolation methods (interpolation functions). The interpolation functions are interpreted as states of a Markov model. In other words, the proposed method undergoes state transitions from one missing pixel position to the next. Accordingly, the interpolation problem is translated to the problem of estimating the optimal sequence of interpolation functions corresponding to the sequence of missing HR pixel positions. We derive a parameter-free probabilistic model for this to-be-estimated sequence of interpolation functions. Then, we solve the estimation problem using a trellis representation and the Viterbi algorithm. Using directional interpolation functions and sequence estimation techniques, we classify the new algorithm as an adaptive directional interpolation using soft-decision estimation techniques. Experimental results show that the proposed algorithm yields images with higher or comparable peak signal-to-noise ratios compared with some benchmark interpolation methods in the literature while being efficient in terms of implementation and complexity considerations.

Kalman Filtering for Genetic Regulatory Networks with Missing Values

PubMed Central

Liu, Qiuhua; Lai, Tianyue; Wang, Wu

2017-01-01

The filter problem with missing value for genetic regulation networks (GRNs) is addressed, in which the noises exist in both the state dynamics and measurement equations; furthermore, the correlation between process noise and measurement noise is also taken into consideration. In order to deal with the filter problem, a class of discrete-time GRNs with missing value, noise correlation, and time delays is established. Then a new observation model is proposed to decrease the adverse effect caused by the missing value and to decouple the correlation between process noise and measurement noise in theory. Finally, a Kalman filtering is used to estimate the states of GRNs. Meanwhile, a typical example is provided to verify the effectiveness of the proposed method, and it turns out to be the case that the concentrations of mRNA and protein could be estimated accurately. PMID:28814967

Lynch Syndrome: Genomics Update and Imaging Review.

PubMed

Cox, Veronica L; Saeed Bamashmos, Anas A; Foo, Wai Chin; Gupta, Shiva; Yedururi, Sireesha; Garg, Naveen; Kang, Hyunseon Christine

2018-01-01

Lynch syndrome is the most common hereditary cancer syndrome, the most common cause of heritable colorectal cancer, and the only known heritable cause of endometrial cancer. Other cancers associated with Lynch syndrome include cancers of the ovary, stomach, urothelial tract, and small bowel, and less frequently, cancers of the brain, biliary tract, pancreas, and prostate. The oncogenic tendency of Lynch syndrome stems from a set of genomic alterations of mismatch repair proteins. Defunct mismatch repair proteins cause unusually high instability of regions of the genome called microsatellites. Over time, the accumulation of mutations in microsatellites and elsewhere in the genome can affect the production of important cellular proteins, spurring tumorigenesis. Universal testing of colorectal tumors for microsatellite instability (MSI) is now recommended to (a) prevent cases of Lynch syndrome being missed owing to the use of clinical criteria alone, (b) reduce morbidity and mortality among the relatives of affected individuals, and (c) guide management decisions. Organ-specific cancer risks and associated screening paradigms vary according to the sex of the affected individual and the type of germline DNA alteration causing the MSI. Furthermore, Lynch syndrome-associated cancers have different pathologic, radiologic, and clinical features compared with their sporadic counterparts. Most notably, Lynch syndrome-associated tumors tend to be more indolent than non-Lynch syndrome-associated neoplasms and thus may respond differently to traditional chemotherapy regimens. The high MSI in cases of colorectal cancer reflects a difference in the biologic features of the tumor, possibly with a unique susceptibility to immunotherapy. © RSNA, 2018.

Mixed Model Association with Family-Biased Case-Control Ascertainment.

PubMed

Hayeck, Tristan J; Loh, Po-Ru; Pollack, Samuela; Gusev, Alexander; Patterson, Nick; Zaitlen, Noah A; Price, Alkes L

2017-01-05

Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow-sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case-control ascertainment, LT-Fam was correctly calibrated (average χ 2 = 1.00-1.02 for null SNPs), whereas the Armitage trend test (ATT), standard mixed model association (MLM), and case-control retrospective association test (CARAT) were mis-calibrated (e.g., average χ 2 = 0.50-1.22 for MLM, 0.89-2.65 for CARAT). LT-Fam also attained higher power than other methods in some settings. In 1,259 type 2 diabetes-affected case subjects and 5,765 control subjects from the CARe cohort, downsampled to induce family-biased ascertainment, LT-Fam was correctly calibrated whereas ATT, MLM, and CARAT were again mis-calibrated. Our results highlight the importance of modeling family sampling bias in case-control datasets with related samples. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Missing Children's Assistance Act. Hearings before the Subcommittee on Juvenile Justice of the Committee on the Judiciary. United States Senate. Ninety-Eighth Congress, Second Session on S. 2014, a Bill to Amend the Juvenile Justice and Delinquency Prevention Act of 1974 to Provide for Assistance in Locating Missing Children (February 7 and 21; March 8, 13, and 21, 1984).

ERIC Educational Resources Information Center

Congress of the U.S., Washington, DC. Senate Committee on the Judiciary.

This document presents testimony and proceedings from Congressional hearings on the problem of missing children and the remedies proposed by the Missing Children's Assistance Act. Opening testimony by Senators Arlen Specter and Paula Hawkins is presented, as is the text of the Missing Children's Assistance Act of 1983. Prepared testimony from…

Integrating Multiple Correlated Phenotypes for Genetic Association Analysis by Maximizing Heritability

PubMed Central

Zhou, Jin J.; Cho, Michael H.; Lange, Christoph; Lutz, Sharon; Silverman, Edwin K.; Laird, Nan M.

2015-01-01

Many correlated disease variables are analyzed jointly in genetic studies in the hope of increasing power to detect causal genetic variants. One approach involves assessing the relationship between each phenotype and each single nucleotide polymorphism (SNP) individually and using a Bonferroni correction for the effective number of tests conducted. Alternatively, one can apply a multivariate regression or a dimension reduction technique, such as principal component analysis (PCA), and test for the association with the principal components (PC) of the phenotypes rather than the individual phenotypes. Inspired by the previous approaches of combining phenotypes to maximize heritability at individual SNPs, in this paper, we propose to construct a maximally heritable phenotype (MaxH) by taking advantage of the estimated total heritability and co-heritability. The heritability and co-heritability only need to be estimated once, therefore our method is applicable to genome-wide scans. MaxH phenotype is a linear combination of the individual phenotypes with increased heritability and power over the phenotypes being combined. Simulations show that the heritability and power achieved agree well with the theory for large samples and two phenotypes. We compare our approach with commonly used methods and assess both the heritability and the power of the MaxH phenotype. Moreover we provide suggestions for how to choose the phenotypes for combination. An application of our approach to a COPD genome-wide association study shows the practical relevance. PMID:26111731

Empirical Likelihood in Nonignorable Covariate-Missing Data Problems.

PubMed

Xie, Yanmei; Zhang, Biao

2017-04-20

Missing covariate data occurs often in regression analysis, which frequently arises in the health and social sciences as well as in survey sampling. We study methods for the analysis of a nonignorable covariate-missing data problem in an assumed conditional mean function when some covariates are completely observed but other covariates are missing for some subjects. We adopt the semiparametric perspective of Bartlett et al. (Improving upon the efficiency of complete case analysis when covariates are MNAR. Biostatistics 2014;15:719-30) on regression analyses with nonignorable missing covariates, in which they have introduced the use of two working models, the working probability model of missingness and the working conditional score model. In this paper, we study an empirical likelihood approach to nonignorable covariate-missing data problems with the objective of effectively utilizing the two working models in the analysis of covariate-missing data. We propose a unified approach to constructing a system of unbiased estimating equations, where there are more equations than unknown parameters of interest. One useful feature of these unbiased estimating equations is that they naturally incorporate the incomplete data into the data analysis, making it possible to seek efficient estimation of the parameter of interest even when the working regression function is not specified to be the optimal regression function. We apply the general methodology of empirical likelihood to optimally combine these unbiased estimating equations. We propose three maximum empirical likelihood estimators of the underlying regression parameters and compare their efficiencies with other existing competitors. We present a simulation study to compare the finite-sample performance of various methods with respect to bias, efficiency, and robustness to model misspecification. The proposed empirical likelihood method is also illustrated by an analysis of a data set from the US National Health and Nutrition Examination Survey (NHANES).

Quantifying the uncertainty in heritability.

PubMed

Furlotte, Nicholas A; Heckerman, David; Lippert, Christoph

2014-05-01

The use of mixed models to determine narrow-sense heritability and related quantities such as SNP heritability has received much recent attention. Less attention has been paid to the inherent variability in these estimates. One approach for quantifying variability in estimates of heritability is a frequentist approach, in which heritability is estimated using maximum likelihood and its variance is quantified through an asymptotic normal approximation. An alternative approach is to quantify the uncertainty in heritability through its Bayesian posterior distribution. In this paper, we develop the latter approach, make it computationally efficient and compare it to the frequentist approach. We show theoretically that, for a sufficiently large sample size and intermediate values of heritability, the two approaches provide similar results. Using the Atherosclerosis Risk in Communities cohort, we show empirically that the two approaches can give different results and that the variance/uncertainty can remain large.

Menstrual Cycle Problems

MedlinePlus

... MoreDepression in Children and TeensRead MoreBMI Calculator Menstrual Cycle ProblemsFrom missed periods to painful periods, menstrual cycle problems are common, but usually not serious. Follow ...

Missing value imputation: with application to handwriting data

NASA Astrophysics Data System (ADS)

Xu, Zhen; Srihari, Sargur N.

2015-01-01

Missing values make pattern analysis difficult, particularly with limited available data. In longitudinal research, missing values accumulate, thereby aggravating the problem. Here we consider how to deal with temporal data with missing values in handwriting analysis. In the task of studying development of individuality of handwriting, we encountered the fact that feature values are missing for several individuals at several time instances. Six algorithms, i.e., random imputation, mean imputation, most likely independent value imputation, and three methods based on Bayesian network (static Bayesian network, parameter EM, and structural EM), are compared with children's handwriting data. We evaluate the accuracy and robustness of the algorithms under different ratios of missing data and missing values, and useful conclusions are given. Specifically, static Bayesian network is used for our data which contain around 5% missing data to provide adequate accuracy and low computational cost.

What to Do when Data Are Missing in Group Randomized Controlled Trials. NCEE 2009-0049

ERIC Educational Resources Information Center

Puma, Michael J.; Olsen, Robert B.; Bell, Stephen H.; Price, Cristofer

2009-01-01

This NCEE Technical Methods report examines how to address the problem of missing data in the analysis of data in Randomized Controlled Trials (RCTs) of educational interventions, with a particular focus on the common educational situation in which groups of students such as entire classrooms or schools are randomized. Missing outcome data are a…

Working with Missing Data in Higher Education Research: A Primer and Real-World Example

ERIC Educational Resources Information Center

Cox, Bradley E.; McIntosh, Kadian; Reason, Robert D.; Terenzini, Patrick T.

2014-01-01

Nearly all quantitative analyses in higher education draw from incomplete datasets-a common problem with no universal solution. In the first part of this paper, we explain why missing data matter and outline the advantages and disadvantages of six common methods for handling missing data. Next, we analyze real-world data from 5,905 students across…

Postmodeling Sensitivity Analysis to Detect the Effect of Missing Data Mechanisms

ERIC Educational Resources Information Center

Jamshidian, Mortaza; Mata, Matthew

2008-01-01

Incomplete or missing data is a common problem in almost all areas of empirical research. It is well known that simple and ad hoc methods such as complete case analysis or mean imputation can lead to biased and/or inefficient estimates. The method of maximum likelihood works well; however, when the missing data mechanism is not one of missing…

75 FR 68802 - Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-09

... Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting In accordance with... following meeting: Name: Secretary's Advisory Committee on Heritable Disorders in Newborns and Children... Committee on Heritable Disorders in Newborns and Children (Advisory Committee) was established to advise and...

Modeling missing data in knowledge space theory.

PubMed

de Chiusole, Debora; Stefanutti, Luca; Anselmi, Pasquale; Robusto, Egidio

2015-12-01

Missing data are a well known issue in statistical inference, because some responses may be missing, even when data are collected carefully. The problem that arises in these cases is how to deal with missing data. In this article, the missingness is analyzed in knowledge space theory, and in particular when the basic local independence model (BLIM) is applied to the data. Two extensions of the BLIM to missing data are proposed: The former, called ignorable missing BLIM (IMBLIM), assumes that missing data are missing completely at random; the latter, called missing BLIM (MissBLIM), introduces specific dependencies of the missing data on the knowledge states, thus assuming that the missing data are missing not at random. The IMBLIM and the MissBLIM modeled the missingness in a satisfactory way, in both a simulation study and an empirical application, depending on the process that generates the missingness: If the missing data-generating process is of type missing completely at random, then either IMBLIM or MissBLIM provide adequate fit to the data. However, if the pattern of missingness is functionally dependent upon unobservable features of the data (e.g., missing answers are more likely to be wrong), then only a correctly specified model of the missingness distribution provides an adequate fit to the data. (c) 2015 APA, all rights reserved).

Fitting the multitemporal curve: a fourier series approach to the missing data problem in remote sensing analysis

Treesearch

Evan Brooks; Valerie Thomas; Wynne Randolph; John Coulston

2012-01-01

With the advent of free Landsat data stretching back decades, there has been a surge of interest in utilizing remotely sensed data in multitemporal analysis for estimation of biophysical parameters. Such analysis is confounded by cloud cover and other image-specific problems, which result in missing data at various aperiodic times of the year. While there is a wealth...

Detection of gene–environment interaction in pedigree data using genome-wide genotypes

PubMed Central

Nivard, Michel G; Middeldorp, Christel M; Lubke, Gitta; Hottenga, Jouke-Jan; Abdellaoui, Abdel; Boomsma, Dorret I; Dolan, Conor V

2016-01-01

Heritability may be estimated using phenotypic data collected in relatives or in distantly related individuals using genome-wide single nucleotide polymorphism (SNP) data. We combined these approaches by re-parameterizing the model proposed by Zaitlen et al and extended this model to include moderation of (total and SNP-based) genetic and environmental variance components by a measured moderator. By means of data simulation, we demonstrated that the type 1 error rates of the proposed test are correct and parameter estimates are accurate. As an application, we considered the moderation by age or year of birth of variance components associated with body mass index (BMI), height, attention problems (AP), and symptoms of anxiety and depression. The genetic variance of BMI was found to increase with age, but the environmental variance displayed a greater increase with age, resulting in a proportional decrease of the heritability of BMI. Environmental variance of height increased with year of birth. The environmental variance of AP increased with age. These results illustrate the assessment of moderation of environmental and genetic effects, when estimating heritability from combined SNP and family data. The assessment of moderation of genetic and environmental variance will enhance our understanding of the genetic architecture of complex traits. PMID:27436263

Different Origin of Auditory and Phonological Processing Problems in Children with Language Impairment: Evidence from a Twin Study.

ERIC Educational Resources Information Center

Bishop, D. V. M.; Bishop, Sonia J.; Bright, Peter; James, Cheryl; Delaney, Tom; Tallal, Paula

1999-01-01

A study involving 55 children with a language impairment and 76 with normal language investigated the heritability of auditory processing impairment in same-sex twins (ages 7 to 13, selected from a sample of 37 pairs). Although correlations between co-twins were high, lack of significant difference between monozygotic and dizygotic twins suggested…

The Promises and Pitfalls of Genoeconomics*

PubMed Central

Benjamin, Daniel J.; Cesarini, David; Chabris, Christopher F.; Glaeser, Edward L.; Laibson, David I.; Guðnason, Vilmundur; Harris, Tamara B.; Launer, Lenore J.; Purcell, Shaun; Smith, Albert Vernon; Johannesson, Magnus; Magnusson, Patrik K.E.; Beauchamp, Jonathan P.; Christakis, Nicholas A.; Atwood, Craig S.; Hebert, Benjamin; Freese, Jeremy; Hauser, Robert M.; Hauser, Taissa S.; Grankvist, Alexander; Hultman, Christina M.; Lichtenstein, Paul

2012-01-01

This article reviews existing research at the intersection of genetics and economics, presents some new findings that illustrate the state of genoeconomics research, and surveys the prospects of this emerging field. Twin studies suggest that economic outcomes and preferences, once corrected for measurement error, appear to be about as heritable as many medical conditions and personality traits. Consistent with this pattern, we present new evidence on the heritability of permanent income and wealth. Turning to genetic association studies, we survey the main ways that the direct measurement of genetic variation across individuals is likely to contribute to economics, and we outline the challenges that have slowed progress in making these contributions. The most urgent problem facing researchers in this field is that most existing efforts to find associations between genetic variation and economic behavior are based on samples that are too small to ensure adequate statistical power. This has led to many false positives in the literature. We suggest a number of possible strategies to improve and remedy this problem: (a) pooling data sets, (b) using statistical techniques that exploit the greater information content of many genes considered jointly, and (c) focusing on economically relevant traits that are most proximate to known biological mechanisms. PMID:23482589

Evidence for a Heritable Brain Basis to Deviance-Promoting Deficits in Self-Control.

PubMed

Yancey, James R; Venables, Noah C; Hicks, Brian M; Patrick, Christopher J

2013-01-01

Classic criminological theories emphasize the role of impaired self-control in behavioral deviancy. Reduced amplitude of the P300 brain response is reliably observed in individuals with antisocial and substance-related problems, suggesting it may serve as a neurophysiological indicator of deficiencies in self-control that confer liability to deviancy. The current study evaluated the role of self-control capacity - operationalized by scores on a scale measure of trait disinhibition - in mediating the relationship between P300 brain response and behavioral deviancy in a sample of adult twins ( N =419) assessed for symptoms of antisocial/addictive disorders and P300 brain response. As predicted, greater disorder symptoms and higher trait disinhibition scores each predicted smaller P300 amplitude, and trait disinhibition mediated observed relations between antisocial/addictive disorders and P300 response. Further, twin modeling analyses revealed that trait disinhibition scores and disorder symptoms reflected a common genetic liability, and this genetic liability largely accounted for the observed phenotypic relationship between antisocial-addictive problems and P300 brain response. These results provide further evidence that heritable weaknesses in self-control capacity confer liability to antisocial/addictive outcomes and that P300 brain response indexes this dispositional liability.

Quantifying the uncertainty in heritability

PubMed Central

Furlotte, Nicholas A; Heckerman, David; Lippert, Christoph

2014-01-01

The use of mixed models to determine narrow-sense heritability and related quantities such as SNP heritability has received much recent attention. Less attention has been paid to the inherent variability in these estimates. One approach for quantifying variability in estimates of heritability is a frequentist approach, in which heritability is estimated using maximum likelihood and its variance is quantified through an asymptotic normal approximation. An alternative approach is to quantify the uncertainty in heritability through its Bayesian posterior distribution. In this paper, we develop the latter approach, make it computationally efficient and compare it to the frequentist approach. We show theoretically that, for a sufficiently large sample size and intermediate values of heritability, the two approaches provide similar results. Using the Atherosclerosis Risk in Communities cohort, we show empirically that the two approaches can give different results and that the variance/uncertainty can remain large. PMID:24670270

Is Spending More Time Associated With Less Missed Care?: A Comparison of Time Use and Missed Care Across 15 Nursing Units at 2 Hospitals.

PubMed

McNair, Norma; Baird, Jennifer; Grogan, Tristan R; Walsh, Catherine M; Liang, Li-Jung; Worobel-Luk, Pamela; Needleman, Jack; Nuckols, Teryl K

2016-09-01

The aim of this study is to examine the relationship between nursing time use and perceptions of missed care. Recent literature has highlighted the problem of missed nursing care, but little is known about how nurses' time use patterns are associated with reports of missed care. In 15 nursing units at 2 hospitals, we assessed registered nurse (RN) perceptions of missed care, observed time use by RNs, and examined the relationship between time spent and degree of missed care at the nursing unit level. Patterns of time use were similar across hospitals, with 25% of time spent on documentation. For 6 different categories of nursing tasks, no association was detected between time use, including time spent on documentation, and the degree of missed care at the nursing unit level. Nursing time use cannot fully explain variation in missed care across nursing units. Further work is needed to account for patterns of missed care.

Quantifying the heritability of testicular germ cell tumour using both population-based and genomic approaches.

PubMed

Litchfield, Kevin; Thomsen, Hauke; Mitchell, Jonathan S; Sundquist, Jan; Houlston, Richard S; Hemminki, Kari; Turnbull, Clare

2015-09-09

A sizable fraction of testicular germ cell tumour (TGCT) risk is expected to be explained by heritable factors. Recent genome-wide association studies (GWAS) have successfully identified a number of common SNPs associated with TGCT. It is however, unclear how much common variation there is left to be accounted for by other, yet to be identified, common SNPs and what contribution common genetic variation makes to the heritable risk of TGCT. We approached this question using two complimentary analytical techniques. We undertook a population-based analysis of the Swedish family-cancer database, through which we estimated that the heritability of TGCT at 48.9% (CI:47.2%-52.3%). We also applied Genome-Wide Complex Trait Analysis to 922 cases and 4,842 controls to estimate the heritability of TGCT. The heritability explained by known common risk SNPs identified by GWAS was 9.1%, whereas the heritability explained by all common SNPs was 37.4% (CI:27.6%-47.2%). These complementary findings indicate that the known TGCT SNPs only explain a small proportion of the heritability and many additional common SNPs remain to be identified. The data also suggests that a fraction of the heritability of TGCT is likely to be explained by other classes of genetic variation, such as rare disease-causing alleles.

Using Extended Genealogy to Estimate Components of Heritability for 23 Quantitative and Dichotomous Traits

PubMed Central

Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L.

2013-01-01

Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays. PMID:23737753

Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits.

PubMed

Zaitlen, Noah; Kraft, Peter; Patterson, Nick; Pasaniuc, Bogdan; Bhatia, Gaurav; Pollack, Samuela; Price, Alkes L

2013-05-01

Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays.

Heritability of anti-predatory traits: vigilance and locomotor performance in marmots.

PubMed

Blumstein, D T; Lea, A J; Olson, L E; Martin, J G A

2010-05-01

Animals must allocate some proportion of their time to detecting predators. In birds and mammals, such anti-predator vigilance has been well studied, and we know that it may be influenced by a variety of intrinsic and extrinsic factors. Despite hundreds of studies focusing on vigilance and suggestions that there are individual differences in vigilance, there have been no prior studies examining its heritability in the field. Here, we present one of the first reports of (additive) genetic variation in vigilance. Using a restricted maximum likelihood procedure, we found that, in yellow-bellied marmots (Marmota flaviventris), the heritability of locomotor ability (h(2)=0.21), and especially vigilance (h(2) = 0.08), is low. These modest heritability estimates suggest great environmental variation or a history of directional selection eliminating genetic variation in these traits. We also found a significant phenotypic (r(P) = -0.09 +/- 0.04, P = 0.024) and a substantial, but not significant, genetic correlation (r(A) = -0.57 +/- 0.28, P = 0.082) between the two traits (slower animals are less vigilant while foraging). We found no evidence of differential survival or longevity associated with particular phenotypes of either trait. The genetic correlation may persist because of environmental heterogeneity and genotype-by-environment interactions maintaining the correlation, or because there are two ways to solve the problem of foraging in exposed areas: be very vigilant and rely on early detection coupled with speed to escape, or reduce vigilance to minimize time spent in an exposed location. Both strategies seem to be equally successful, and this 'locomotor ability-wariness' syndrome may therefore allow slow animals to compensate behaviourally for their impaired locomotor ability.

Considerations of multiple imputation approaches for handling missing data in clinical trials.

PubMed

Quan, Hui; Qi, Li; Luo, Xiaodong; Darchy, Loic

2018-07-01

Missing data exist in all clinical trials and missing data issue is a very serious issue in terms of the interpretability of the trial results. There is no universally applicable solution for all missing data problems. Methods used for handling missing data issue depend on the circumstances particularly the assumptions on missing data mechanisms. In recent years, if the missing at random mechanism cannot be assumed, conservative approaches such as the control-based and returning to baseline multiple imputation approaches are applied for dealing with the missing data issues. In this paper, we focus on the variability in data analysis of these approaches. As demonstrated by examples, the choice of the variability can impact the conclusion of the analysis. Besides the methods for continuous endpoints, we also discuss methods for binary and time to event endpoints as well as consideration for non-inferiority assessment. Copyright © 2018. Published by Elsevier Inc.

The Effect of a Brief Acceptance and Commitment Therapy Intervention on the Near-Miss Effect in Problem Gamblers

ERIC Educational Resources Information Center

Nastally, Becky L.; Dixon, Mark R.

2012-01-01

In the current study, 3 participants with a history of problem gambling were exposed to computerized slot machine play consisting of outcomes that depicted wins, losses, and near misses (2 out of 3 identical slot machine symbols). Participants were asked to rate each type of outcome in terms of its closeness to a win on a scale of 1 to 10 before…

Autoregressive-model-based missing value estimation for DNA microarray time series data.

PubMed

Choong, Miew Keen; Charbit, Maurice; Yan, Hong

2009-01-01

Missing value estimation is important in DNA microarray data analysis. A number of algorithms have been developed to solve this problem, but they have several limitations. Most existing algorithms are not able to deal with the situation where a particular time point (column) of the data is missing entirely. In this paper, we present an autoregressive-model-based missing value estimation method (ARLSimpute) that takes into account the dynamic property of microarray temporal data and the local similarity structures in the data. ARLSimpute is especially effective for the situation where a particular time point contains many missing values or where the entire time point is missing. Experiment results suggest that our proposed algorithm is an accurate missing value estimator in comparison with other imputation methods on simulated as well as real microarray time series datasets.

Heritable and non-heritable pathways to early callous-unemotional behaviors

PubMed Central

Hyde, Luke W.; Waller, Rebecca; Trentacosta, Christopher J.; Shaw, Daniel S.; Neiderhiser, Jenae M.; Ganiban, Jody M.; Reiss, David; Leve, Leslie D.

2016-01-01

Objective Callous-unemotional behaviors in early childhood identify children at high risk for severe trajectories of antisocial behavior and callous-unemotional traits that culminate in later diagnoses of conduct disorder, antisocial personality disorder, and psychopathy. Studies have demonstrated high heritability of callous-unemotional traits, but little research has examined specific heritable pathways to earlier callous-unemotional behaviors. Additionally, studies indicate that positive parenting protects against the development of callous-unemotional traits, but genetically informed designs have not been used to confirm that these relationships are not the product of gene-environment correlations. Method Using an adoption cohort of 561 families, biological mothers reported their history of severe antisocial behavior. Observations of adoptive mother positive reinforcement at 18 months were examined as predictors of callous-unemotional behaviors when children were 27 months old. Results Biological mother antisocial behavior predicted early callous-unemotional behaviors despite having no or limited contact with offspring. Adoptive mother positive reinforcement protected against early callous-unemotional behaviors in children not genetically related to the parent. High levels of adoptive mother positive reinforcement buffered the effects of heritable risk for callous-unemotional behaviors posed by biological mother antisocial behavior. Conclusions The findings elucidate heritable and non-heritable pathways to early callous-unemotional behaviors. The results provide a specific heritable pathway to callous-unemotional behaviors and compelling evidence that parenting is an important non-heritable factor in the development of callous-unemotional behaviors. As positive reinforcement buffered heritable risk for callous-unemotional behaviors, these findings have important translational implications for the prevention of trajectories to serious antisocial behavior. PMID:27056607

The Impact of the Nursing Practice Environment on Missed Nursing Care.

PubMed

Hessels, Amanda J; Flynn, Linda; Cimiotti, Jeannie P; Cadmus, Edna; Gershon, Robyn R M

2015-12-01

Missed nursing care is an emerging problem negatively impacting patient outcomes. There are gaps in our knowledge of factors associated with missed nursing care. The aim of this study was to determine the relationship between the nursing practice environment and missed nursing care in acute care hospitals. This is a secondary analysis of cross sectional data from a survey of over 7.000 nurses from 70 hospitals on workplace and process of care. Ordinary least squares and multiple regression models were constructed to examine the relationship between the nursing practice environment and missed nursing care while controlling for characteristics of nurses and hospitals. Nurses missed delivering a significant amount of necessary patient care (10-27%). Inadequate staffing and inadequate resources were the practice environment factors most strongly associated with missed nursing care events. This multi-site study examined the risk and risk factors associated with missed nursing care. Improvements targeting modifiable risk factors may reduce the risk of missed nursing care.

Heritability of MMPI-2 scales in the UCSF Family Alcoholism Study

PubMed Central

Gizer, Ian R.; Seaton-Smith, Kimberley L.; Ehlers, Cindy L.; Vietan, Cassandra; Wilhelmsen, Kirk C.

2009-01-01

The present study evaluated the heritability of personality traits and psychopathology symptoms assessed by the Minnesota Multiphasic Personality Interview 2nd edition (MMPI-2) in a family-based sample selected for alcohol dependence. Participants included 950 probands and 1204 first-degree relatives recruited for the UCSF Family Alcoholism Study. Heritability estimates (h2) for MMPI-2 scales ranged from .25–.49. When alcohol dependence was used as a covariate, heritability estimates remained significant but generally declined. However, when the MMPI-2 scales were used as covariates to estimate the heritability of alcohol dependence, scales measuring antisocial behavior (ASP), depressive symptoms (DEP), and addictive behavior (MAC-R) led to moderate increases in the heritability of alcohol dependence. This suggests that the ASP, DEP, and MAC-R scales may explain some of the non-genetic variance in the alcohol dependence diagnosis in this population when utilized as covariates, and thus may serve to produce a more homogeneous and heritable alcohol dependence phenotype. PMID:20390702

Partitioning heritability by functional annotation using genome-wide association summary statistics.

PubMed

Finucane, Hilary K; Bulik-Sullivan, Brendan; Gusev, Alexander; Trynka, Gosia; Reshef, Yakir; Loh, Po-Ru; Anttila, Verneri; Xu, Han; Zang, Chongzhi; Farh, Kyle; Ripke, Stephan; Day, Felix R; Purcell, Shaun; Stahl, Eli; Lindstrom, Sara; Perry, John R B; Okada, Yukinori; Raychaudhuri, Soumya; Daly, Mark J; Patterson, Nick; Neale, Benjamin M; Price, Alkes L

2015-11-01

Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.

The Origins of Diverse Domains of Mathematics: Generalist Genes but Specialist Environments

ERIC Educational Resources Information Center

Kovas, Y.; Petrill, S. A.; Plomin, R.

2007-01-01

The authors assessed 2,502 ten-year-old children, members of 1,251 pairs of twins, on a Web-based battery of problems from 5 diverse aspects of mathematics assessed as part of the U.K. national curriculum. This 1st genetic study into the etiology of variation in different domains of mathematics showed that the heritability estimates were moderate…

Application of a novel hybrid method for spatiotemporal data imputation: A case study of the Minqin County groundwater level

NASA Astrophysics Data System (ADS)

Zhang, Zhongrong; Yang, Xuan; Li, Hao; Li, Weide; Yan, Haowen; Shi, Fei

2017-10-01

The techniques for data analyses have been widely developed in past years, however, missing data still represent a ubiquitous problem in many scientific fields. In particular, dealing with missing spatiotemporal data presents an enormous challenge. Nonetheless, in recent years, a considerable amount of research has focused on spatiotemporal problems, making spatiotemporal missing data imputation methods increasingly indispensable. In this paper, a novel spatiotemporal hybrid method is proposed to verify and imputed spatiotemporal missing values. This new method, termed SOM-FLSSVM, flexibly combines three advanced techniques: self-organizing feature map (SOM) clustering, the fruit fly optimization algorithm (FOA) and the least squares support vector machine (LSSVM). We employ a cross-validation (CV) procedure and FOA swarm intelligence optimization strategy that can search available parameters and determine the optimal imputation model. The spatiotemporal underground water data for Minqin County, China, were selected to test the reliability and imputation ability of SOM-FLSSVM. We carried out a validation experiment and compared three well-studied models with SOM-FLSSVM using a different missing data ratio from 0.1 to 0.8 in the same data set. The results demonstrate that the new hybrid method performs well in terms of both robustness and accuracy for spatiotemporal missing data.

Simulation-based sensitivity analysis for non-ignorably missing data.

PubMed

Yin, Peng; Shi, Jian Q

2017-01-01

Sensitivity analysis is popular in dealing with missing data problems particularly for non-ignorable missingness, where full-likelihood method cannot be adopted. It analyses how sensitively the conclusions (output) may depend on assumptions or parameters (input) about missing data, i.e. missing data mechanism. We call models with the problem of uncertainty sensitivity models. To make conventional sensitivity analysis more useful in practice we need to define some simple and interpretable statistical quantities to assess the sensitivity models and make evidence based analysis. We propose a novel approach in this paper on attempting to investigate the possibility of each missing data mechanism model assumption, by comparing the simulated datasets from various MNAR models with the observed data non-parametrically, using the K-nearest-neighbour distances. Some asymptotic theory has also been provided. A key step of this method is to plug in a plausibility evaluation system towards each sensitivity parameter, to select plausible values and reject unlikely values, instead of considering all proposed values of sensitivity parameters as in the conventional sensitivity analysis method. The method is generic and has been applied successfully to several specific models in this paper including meta-analysis model with publication bias, analysis of incomplete longitudinal data and mean estimation with non-ignorable missing data.

A novel approach for incremental uncertainty rule generation from databases with missing values handling: application to dynamic medical databases.

PubMed

Konias, Sokratis; Chouvarda, Ioanna; Vlahavas, Ioannis; Maglaveras, Nicos

2005-09-01

Current approaches for mining association rules usually assume that the mining is performed in a static database, where the problem of missing attribute values does not practically exist. However, these assumptions are not preserved in some medical databases, like in a home care system. In this paper, a novel uncertainty rule algorithm is illustrated, namely URG-2 (Uncertainty Rule Generator), which addresses the problem of mining dynamic databases containing missing values. This algorithm requires only one pass from the initial dataset in order to generate the item set, while new metrics corresponding to the notion of Support and Confidence are used. URG-2 was evaluated over two medical databases, introducing randomly multiple missing values for each record's attribute (rate: 5-20% by 5% increments) in the initial dataset. Compared with the classical approach (records with missing values are ignored), the proposed algorithm was more robust in mining rules from datasets containing missing values. In all cases, the difference in preserving the initial rules ranged between 30% and 60% in favour of URG-2. Moreover, due to its incremental nature, URG-2 saved over 90% of the time required for thorough re-mining. Thus, the proposed algorithm can offer a preferable solution for mining in dynamic relational databases.

Consequences of severe obstetric complications on women's health in Morocco: please, listen to me!

PubMed

Assarag, Bouchra; Dujardin, Bruno; Essolbi, Amina; Cherkaoui, Imad; De Brouwere, Vincent

2015-11-01

In Morocco, medical care for women with severe obstetric complications (near-miss cases) ends at discharge from the hospital. Little information exists regarding what happens after returning home. The aim of the study was to assess the physical and mental health consequences of near-miss events on Moroccan women 8 months after childbirth. A prospective cohort study of 76 near-miss women was conducted in three hospitals. For every case, we recruited at least two women from the same hospital who had uncomplicated deliveries (n = 169). We used a mixed-methods approach. For the quantitative part, we analysed sociodemographic characteristics collected via a questionnaire and medical complications extracted from the medical records during a medical consultation at 8 months post-partum. Forty in-depth interviews were also conducted with 20 near-miss cases and 20 women with uncomplicated deliveries. The near-miss women were poorer and less educated than those who had uncomplicated deliveries. The proportion of physical consequences (serious illness) was higher among near-miss cases (22%) than uncomplicated deliveries (6%, P = 0.001). The risk of depression was significantly higher among near-miss cases with perinatal death (OR = 7.16; [95% CI: 2.85-17.98]) than among those who had an uncomplicated delivery. Interviews revealed that the economic burden of near-miss care contributed to social problems among the women and their households. A near-miss event has consequences that go beyond the first days after delivery. Developing new mechanisms for maternal and newborn health follow-up is essential and should address the mother's physical and mental health problems and involve husbands and family members. © 2015 The Authors. Tropical Medicine & International Health Published by John Wiley & Sons Ltd.

Data Quality and Reliability Analysis of U.S. Marine Corps Ground Vehicle Maintenance Records

DTIC Science & Technology

2015-06-01

Corporation conducted a study on data quality issues present in U. S. Army logistics data ( Galway & Hanks, 1996). The study breaks data issues into three...categories: operational, conceptual, and organizational problems ( Galway & Hanks, 1996). Operational data problems relate to the number of missing or...codes (EIC) are left blank ( Galway & Hanks, 1996, p. 26). Missing entries are attributed to an assumed lack of significance of the EIC. The issue is

Causal inference with missing exposure information: Methods and applications to an obstetric study.

PubMed

Zhang, Zhiwei; Liu, Wei; Zhang, Bo; Tang, Li; Zhang, Jun

2016-10-01

Causal inference in observational studies is frequently challenged by the occurrence of missing data, in addition to confounding. Motivated by the Consortium on Safe Labor, a large observational study of obstetric labor practice and birth outcomes, this article focuses on the problem of missing exposure information in a causal analysis of observational data. This problem can be approached from different angles (i.e. missing covariates and causal inference), and useful methods can be obtained by drawing upon the available techniques and insights in both areas. In this article, we describe and compare a collection of methods based on different modeling assumptions, under standard assumptions for missing data (i.e. missing-at-random and positivity) and for causal inference with complete data (i.e. no unmeasured confounding and another positivity assumption). These methods involve three models: one for treatment assignment, one for the dependence of outcome on treatment and covariates, and one for the missing data mechanism. In general, consistent estimation of causal quantities requires correct specification of at least two of the three models, although there may be some flexibility as to which two models need to be correct. Such flexibility is afforded by doubly robust estimators adapted from the missing covariates literature and the literature on causal inference with complete data, and by a newly developed triply robust estimator that is consistent if any two of the three models are correct. The methods are applied to the Consortium on Safe Labor data and compared in a simulation study mimicking the Consortium on Safe Labor. © The Author(s) 2013.

Analysis of Behavioral and Emotional Problems in Children Highlights the Role of Genotype × Environment Interaction.

PubMed

Molenaar, Dylan; Middeldorp, Christel; van Beijsterveldt, Toos; Boomsma, Dorret I

2015-01-01

This study tested for Genotype × Environment (G × E) interaction on behavioral and emotional problems in children using new methods that do not require identification of candidate genes or environments, can distinguish between interaction with shared and unique environment, and are insensitive to scale effects. Parental ratings of problem behavior from 14,755 twin pairs (5.3 years, SD = 0.22) indicated G × E interaction on emotional liability, social isolation, aggression, attention problems, dependency, anxiety, and physical coordination. Environmental influences increased in children who were genetically more predisposed to problem behavior, with ~20% of the variance due to G × E interaction (8% for anxiety to 37% for attention problems). Ignoring G × E interaction does not greatly bias heritability estimates, but it does offer a comprehensive model of the etiology for childhood problems. © 2015 The Authors. Child Development © 2015 Society for Research in Child Development, Inc.

A General Definition of the Heritable Variation That Determines the Potential of a Population to Respond to Selection

PubMed Central

Bijma, Piter

2011-01-01

Genetic selection is a major force shaping life on earth. In classical genetic theory, response to selection is the product of the strength of selection and the additive genetic variance in a trait. The additive genetic variance reflects a population’s intrinsic potential to respond to selection. The ordinary additive genetic variance, however, ignores the social organization of life. With social interactions among individuals, individual trait values may depend on genes in others, a phenomenon known as indirect genetic effects. Models accounting for indirect genetic effects, however, lack a general definition of heritable variation. Here I propose a general definition of the heritable variation that determines the potential of a population to respond to selection. This generalizes the concept of heritable variance to any inheritance model and level of organization. The result shows that heritable variance determining potential response to selection is the variance among individuals in the heritable quantity that determines the population mean trait value, rather than the usual additive genetic component of phenotypic variance. It follows, therefore, that heritable variance may exceed phenotypic variance among individuals, which is impossible in classical theory. This work also provides a measure of the utilization of heritable variation for response to selection and integrates two well-known models of maternal genetic effects. The result shows that relatedness between the focal individual and the individuals affecting its fitness is a key determinant of the utilization of heritable variance for response to selection. PMID:21926298

A general definition of the heritable variation that determines the potential of a population to respond to selection.

PubMed

Bijma, Piter

2011-12-01

Genetic selection is a major force shaping life on earth. In classical genetic theory, response to selection is the product of the strength of selection and the additive genetic variance in a trait. The additive genetic variance reflects a population's intrinsic potential to respond to selection. The ordinary additive genetic variance, however, ignores the social organization of life. With social interactions among individuals, individual trait values may depend on genes in others, a phenomenon known as indirect genetic effects. Models accounting for indirect genetic effects, however, lack a general definition of heritable variation. Here I propose a general definition of the heritable variation that determines the potential of a population to respond to selection. This generalizes the concept of heritable variance to any inheritance model and level of organization. The result shows that heritable variance determining potential response to selection is the variance among individuals in the heritable quantity that determines the population mean trait value, rather than the usual additive genetic component of phenotypic variance. It follows, therefore, that heritable variance may exceed phenotypic variance among individuals, which is impossible in classical theory. This work also provides a measure of the utilization of heritable variation for response to selection and integrates two well-known models of maternal genetic effects. The result shows that relatedness between the focal individual and the individuals affecting its fitness is a key determinant of the utilization of heritable variance for response to selection.

Testing for biases in selection on avian reproductive traits and partitioning direct and indirect selection using quantitative genetic models.

PubMed

Reed, Thomas E; Gienapp, Phillip; Visser, Marcel E

2016-10-01

Key life history traits such as breeding time and clutch size are frequently both heritable and under directional selection, yet many studies fail to document microevolutionary responses. One general explanation is that selection estimates are biased by the omission of correlated traits that have causal effects on fitness, but few valid tests of this exist. Here, we show, using a quantitative genetic framework and six decades of life-history data on two free-living populations of great tits Parus major, that selection estimates for egg-laying date and clutch size are relatively unbiased. Predicted responses to selection based on the Robertson-Price Identity were similar to those based on the multivariate breeder's equation (MVBE), indicating that unmeasured covarying traits were not missing from the analysis. Changing patterns of phenotypic selection on these traits (for laying date, linked to climate change) therefore reflect changing selection on breeding values, and genetic constraints appear not to limit their independent evolution. Quantitative genetic analysis of correlational data from pedigreed populations can be a valuable complement to experimental approaches to help identify whether apparent associations between traits and fitness are biased by missing traits, and to parse the roles of direct versus indirect selection across a range of environments. © 2016 The Author(s). Evolution © 2016 The Society for the Study of Evolution.

JBASE: Joint Bayesian Analysis of Subphenotypes and Epistasis.

PubMed

Colak, Recep; Kim, TaeHyung; Kazan, Hilal; Oh, Yoomi; Cruz, Miguel; Valladares-Salgado, Adan; Peralta, Jesus; Escobedo, Jorge; Parra, Esteban J; Kim, Philip M; Goldenberg, Anna

2016-01-15

Rapid advances in genotyping and genome-wide association studies have enabled the discovery of many new genotype-phenotype associations at the resolution of individual markers. However, these associations explain only a small proportion of theoretically estimated heritability of most diseases. In this work, we propose an integrative mixture model called JBASE: joint Bayesian analysis of subphenotypes and epistasis. JBASE explores two major reasons of missing heritability: interactions between genetic variants, a phenomenon known as epistasis and phenotypic heterogeneity, addressed via subphenotyping. Our extensive simulations in a wide range of scenarios repeatedly demonstrate that JBASE can identify true underlying subphenotypes, including their associated variants and their interactions, with high precision. In the presence of phenotypic heterogeneity, JBASE has higher Power and lower Type 1 Error than five state-of-the-art approaches. We applied our method to a sample of individuals from Mexico with Type 2 diabetes and discovered two novel epistatic modules, including two loci each, that define two subphenotypes characterized by differences in body mass index and waist-to-hip ratio. We successfully replicated these subphenotypes and epistatic modules in an independent dataset from Mexico genotyped with a different platform. JBASE is implemented in C++, supported on Linux and is available at http://www.cs.toronto.edu/∼goldenberg/JBASE/jbase.tar.gz. The genotype data underlying this study are available upon approval by the ethics review board of the Medical Centre Siglo XXI. Please contact Dr Miguel Cruz at mcruzl@yahoo.com for assistance with the application. anna.goldenberg@utoronto.ca Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press.

Genetics of pediatric obesity.

PubMed

Manco, Melania; Dallapiccola, Bruno

2012-07-01

Onset of obesity has been anticipated at earlier ages, and prevalence has dramatically increased worldwide over the past decades. Epidemic obesity is mainly attributable to modern lifestyle, but family studies prove the significant role of genes in the individual's predisposition to obesity. Advances in genotyping technologies have raised great hope and expectations that genetic testing will pave the way to personalized medicine and that complex traits such as obesity will be prevented even before birth. In the presence of the pressing offer of direct-to-consumer genetic testing services from private companies to estimate the individual's risk for complex phenotypes including obesity, the present review offers pediatricians an update of the state of the art on genomics obesity in childhood. Discrepancies with respect to genomics of adult obesity are discussed. After an appraisal of findings from genome-wide association studies in pediatric populations, the rare variant-common disease hypothesis, the theoretical soil for next-generation sequencing techniques, is discussed as opposite to the common disease-common variant hypothesis. Next-generation sequencing techniques are expected to fill the gap of "missing heritability" of obesity, identifying rare variants associated with the trait and clarifying the role of epigenetics in its heritability. Pediatric obesity emerges as a complex phenotype, modulated by unique gene-environment interactions that occur in periods of life and are "permissive" for the programming of adult obesity. With the advent of next-generation sequencing techniques and advances in the field of exposomics, sensitive and specific tools to predict the obesity risk as early as possible are the challenge for the next decade.

GWASeq: targeted re-sequencing follow up to GWAS.

PubMed

Salomon, Matthew P; Li, Wai Lok Sibon; Edlund, Christopher K; Morrison, John; Fortini, Barbara K; Win, Aung Ko; Conti, David V; Thomas, Duncan C; Duggan, David; Buchanan, Daniel D; Jenkins, Mark A; Hopper, John L; Gallinger, Steven; Le Marchand, Loïc; Newcomb, Polly A; Casey, Graham; Marjoram, Paul

2016-03-03

For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.

Late language emergence in 24-month-old twins: heritable and increased risk for late language emergence in twins.

PubMed

Rice, Mabel L; Zubrick, Stephen R; Taylor, Catherine L; Gayán, Javier; Bontempo, Daniel E

2014-06-01

This study investigated the etiology of late language emergence (LLE) in 24-month-old twins, considering possible twinning, zygosity, gender, and heritability effects for vocabulary and grammar phenotypes. A population-based sample of 473 twin pairs participated. Multilevel modeling estimated means and variances of vocabulary and grammar phenotypes, controlling for familiality. Heritability was estimated with DeFries-Fulker regression and variance components models to determine effects of heritability, shared environment, and nonshared environment. Twins had lower average language scores than norms for single-born children, with lower average performance for monozygotic than dizygotic twins and for boys than girls, although gender and zygosity did not interact. Gender did not predict LLE. Significant heritability was detected for vocabulary (0.26) and grammar phenotypes (0.52 and 0.43 for boys and girls, respectively) in the full sample and in the sample selected for LLE (0.42 and 0.44). LLE and the appearance of Word Combinations were also significantly heritable (0.22-0.23). The findings revealed an increased likelihood of LLE in twin toddlers compared with single-born children that is modulated by zygosity and gender differences. Heritability estimates are consistent with previous research for vocabulary and add further suggestion of heritable differences in early grammar acquisition.

A systematic review of the heritability of specific psychopathic traits using Hare's two-factor model of psychopathy.

PubMed

Dhanani, Sapna; Kumari, Veena; Puri, Basant K; Treasaden, Ian; Young, Susan; Sen, Piyal

2018-02-01

There have been no systematic reviews that investigated the heritability of the two-factor model of psychopathy: interpersonal-affective and behavioral. Our review aimed, first, to examine the heritability of general psychopathic traits and, second, if genetic influences were suggested, to determine the heritability of various traits related to the interpersonal-affective and behavioral factors of psychopathy. A systematic literature search was conducted using articles from the PsycINFO, Embase, Global Health, Medline, PubMed, Web of Science, and Scopus databases (January of 1980 to December of 2015) in order to identify eligible literature that reported on the heritability of psychopathy-related traits. Papers were also found via manual examination and reference tracking. Papers were subjected to exclusion criteria and quality appraisal. We identified a total of 24 studies. Our results were grouped into three categories: general, interpersonal-affective, and behavioral. All these areas demonstrated modest to high heritability. The highest heritability values were found in studies investigating callous-unemotional behaviors. Heritability was found for all the psychopathic traits. Future research should include endophenotypic approaches that explore gene-environment correlations, which could aid in identification of the behavioral phenotype that is most amenable to early intervention by way of moderation of genetic risk.

Accounting for missing data in the estimation of contemporary genetic effective population size (N(e) ).

PubMed

Peel, D; Waples, R S; Macbeth, G M; Do, C; Ovenden, J R

2013-03-01

Theoretical models are often applied to population genetic data sets without fully considering the effect of missing data. Researchers can deal with missing data by removing individuals that have failed to yield genotypes and/or by removing loci that have failed to yield allelic determinations, but despite their best efforts, most data sets still contain some missing data. As a consequence, realized sample size differs among loci, and this poses a problem for unbiased methods that must explicitly account for random sampling error. One commonly used solution for the calculation of contemporary effective population size (N(e) ) is to calculate the effective sample size as an unweighted mean or harmonic mean across loci. This is not ideal because it fails to account for the fact that loci with different numbers of alleles have different information content. Here we consider this problem for genetic estimators of contemporary effective population size (N(e) ). To evaluate bias and precision of several statistical approaches for dealing with missing data, we simulated populations with known N(e) and various degrees of missing data. Across all scenarios, one method of correcting for missing data (fixed-inverse variance-weighted harmonic mean) consistently performed the best for both single-sample and two-sample (temporal) methods of estimating N(e) and outperformed some methods currently in widespread use. The approach adopted here may be a starting point to adjust other population genetics methods that include per-locus sample size components. © 2012 Blackwell Publishing Ltd.

Nature or Nurture? Heritability in the Classroom.

PubMed

Hiramatsu, Layla; Garland, Theodore

Understanding evolution is a necessary component of undergraduate education in biology, and evolution is difficult to explain without studying the heritability of traits. However, in most classes, heritability is presented with only a handful of graphs showing typical morphological traits, for example, beak size in finches and height in humans. The active-inquiry exercise outlined in the following pages allows instructors to engage students in this formerly dry subject by bringing their own data as the basis for estimates of heritability. Students are challenged to come up with their own hypotheses regarding how and to what extent their traits are inherited from their parents and then gather, analyze data, and make inferences with help from the instructor. The exercise is simple in concept and execution but uncovers many new avenues of inquiry for students, including potential biases in their estimates of heritability and misconceptions that they may have had about the extent of inference that can be made from their heritability estimates. The active-inquiry format of the exercise prioritizes curiosity and discussion, leading to a much deeper understanding of heritability and the scientific method.

Replacing missing values using trustworthy data values from web data sources

NASA Astrophysics Data System (ADS)

Izham Jaya, M.; Sidi, Fatimah; Mat Yusof, Sharmila; Suriani Affendey, Lilly; Ishak, Iskandar; Jabar, Marzanah A.

2017-09-01

In practice, collected data usually are incomplete and contains missing value. Existing approaches in managing missing values overlook the importance of trustworthy data values in replacing missing values. In view that trusted completed data is very important in data analysis, we proposed a framework of missing value replacement using trustworthy data values from web data sources. The proposed framework adopted ontology to map data values from web data sources to the incomplete dataset. As data from web is conflicting with each other, we proposed a trust score measurement based on data accuracy and data reliability. Trust score is then used to select trustworthy data values from web data sources for missing values replacement. We successfully implemented the proposed framework using financial dataset and presented the findings in this paper. From our experiment, we manage to show that replacing missing values with trustworthy data values is important especially in a case of conflicting data to solve missing values problem.

Transitioning to multiple imputation : a new method to impute missing blood alcohol concentration (BAC) values in FARS

DOT National Transportation Integrated Search

2002-01-01

The National Center for Statistics and Analysis (NCSA) of the National Highway Traffic Safety : Administration (NHTSA) has undertaken several approaches to remedy the problem of missing blood alcohol : test results in the Fatality Analysis Reporting ...

mvp - an open-source preprocessor for cleaning duplicate records and missing values in mass spectrometry data.

PubMed

Lee, Geunho; Lee, Hyun Beom; Jung, Byung Hwa; Nam, Hojung

2017-07-01

Mass spectrometry (MS) data are used to analyze biological phenomena based on chemical species. However, these data often contain unexpected duplicate records and missing values due to technical or biological factors. These 'dirty data' problems increase the difficulty of performing MS analyses because they lead to performance degradation when statistical or machine-learning tests are applied to the data. Thus, we have developed missing values preprocessor (mvp), an open-source software for preprocessing data that might include duplicate records and missing values. mvp uses the property of MS data in which identical chemical species present the same or similar values for key identifiers, such as the mass-to-charge ratio and intensity signal, and forms cliques via graph theory to process dirty data. We evaluated the validity of the mvp process via quantitative and qualitative analyses and compared the results from a statistical test that analyzed the original and mvp-applied data. This analysis showed that using mvp reduces problems associated with duplicate records and missing values. We also examined the effects of using unprocessed data in statistical tests and examined the improved statistical test results obtained with data preprocessed using mvp.

Missed and Delayed Diagnosis of Dementia in Primary Care: Prevalence and Contributing Factors

PubMed Central

Bradford, Andrea; Kunik, Mark E.; Schulz, Paul; Williams, Susan P.; Singh, Hardeep

2009-01-01

Dementia is a growing public health problem for which early detection may be beneficial. Currently, the diagnosis of dementia in primary care is dependent mostly on clinical suspicion based on patient symptomsor caregivers’ concerns and is prone to be missed or delayed. We conducted a systematic review of the literature to ascertain the prevalence and contributing factors for missed and delayed dementia diagnoses in primary care. Prevalence of missed and delayed diagnosis was estimated by abstracting quantitative data from studies of diagnostic sensitivity among primary care providers. Possible predictors and contributory factors were determined from the text of quantitative and qualitative studies of patient-, caregiver-, provider-, and system-related barriers. Overall estimates of diagnostic sensitivity varied among studies and appeared to be in part a function of dementia severity, degree of patient impairment, dementia subtype, and frequency of patient-provider contact. Major contributory factors included problems with attitudes and patient-provider communication, educational deficits, and system resource constraints. The true prevalence of missed and delayed diagnoses of dementia is unknown but appears to be high. Until the case for dementia screening becomes more compelling, efforts to promote timely detection should focus on removing barriers to diagnosis. PMID:19568149

Avoiding pitfalls in estimating heritability with the common options approach

PubMed Central

Danchin, Etienne; Wajnberg, Eric; Wagner, Richard H.

2014-01-01

In many circumstances, heritability estimates are subject to two potentially interacting pitfalls: the spatial and the regression to the mean (RTM) fallacies. The spatial fallacy occurs when the set of potential movement options differs among individuals according to where individuals depart. The RTM fallacy occurs when extreme measurements are followed by measurements that are closer to the mean. We simulated data from the largest published heritability study of a behavioural trait, colony size choice, to examine the operation of the two fallacies. We found that spurious heritabilities are generated under a wide range of conditions both in experimental and correlative estimates of heritability. Classically designed cross-foster experiments can actually increase the frequency of spurious heritabilities. Simulations showed that experiments providing all individuals with the identical set of options, such as by fostering all offspring in the same breeding location, are immune to the two pitfalls. PMID:24865284

Evidence for a Heritable Brain Basis to Deviance-Promoting Deficits in Self-Control

PubMed Central

Yancey, James R.; Venables, Noah C.; Hicks, Brian M.; Patrick, Christopher J.

2013-01-01

Purpose Classic criminological theories emphasize the role of impaired self-control in behavioral deviancy. Reduced amplitude of the P300 brain response is reliably observed in individuals with antisocial and substance-related problems, suggesting it may serve as a neurophysiological indicator of deficiencies in self-control that confer liability to deviancy. Methods The current study evaluated the role of self-control capacity — operationalized by scores on a scale measure of trait disinhibition — in mediating the relationship between P300 brain response and behavioral deviancy in a sample of adult twins (N=419) assessed for symptoms of antisocial/addictive disorders and P300 brain response. Results As predicted, greater disorder symptoms and higher trait disinhibition scores each predicted smaller P300 amplitude, and trait disinhibition mediated observed relations between antisocial/addictive disorders and P300 response. Further, twin modeling analyses revealed that trait disinhibition scores and disorder symptoms reflected a common genetic liability, and this genetic liability largely accounted for the observed phenotypic relationship between antisocial-addictive problems and P300 brain response. Conclusions These results provide further evidence that heritable weaknesses in self-control capacity confer liability to antisocial/addictive outcomes and that P300 brain response indexes this dispositional liability. PMID:24187392

Sensitivity Analysis of Multiple Informant Models When Data are Not Missing at Random

PubMed Central

Blozis, Shelley A.; Ge, Xiaojia; Xu, Shu; Natsuaki, Misaki N.; Shaw, Daniel S.; Neiderhiser, Jenae; Scaramella, Laura; Leve, Leslie; Reiss, David

2014-01-01

Missing data are common in studies that rely on multiple informant data to evaluate relationships among variables for distinguishable individuals clustered within groups. Estimation of structural equation models using raw data allows for incomplete data, and so all groups may be retained even if only one member of a group contributes data. Statistical inference is based on the assumption that data are missing completely at random or missing at random. Importantly, whether or not data are missing is assumed to be independent of the missing data. A saturated correlates model that incorporates correlates of the missingness or the missing data into an analysis and multiple imputation that may also use such correlates offer advantages over the standard implementation of SEM when data are not missing at random because these approaches may result in a data analysis problem for which the missingness is ignorable. This paper considers these approaches in an analysis of family data to assess the sensitivity of parameter estimates to assumptions about missing data, a strategy that may be easily implemented using SEM software. PMID:25221420

Modeling genetic and environmental factors to increase heritability and ease the identification of candidate genes for birth weight: a twin study.

PubMed

Gielen, M; Lindsey, P J; Derom, C; Smeets, H J M; Souren, N Y; Paulussen, A D C; Derom, R; Nijhuis, J G

2008-01-01

Heritability estimates of birth weight have been inconsistent. Possible explanations are heritability changes during gestational age or the influence of covariates (e.g. chorionicity). The aim of this study was to model birth weights of twins across gestational age and to quantify the genetic and environmental components. We intended to reduce the common environmental variance to increase heritability and thereby the chance of identifying candidate genes influencing the genetic variance of birth weight. Perinatal data were obtained from 4232 live-born twin pairs from the East Flanders Prospective Twin Survey, Belgium. Heritability of birth weights across gestational ages was estimated using a non-linear multivariate Gaussian regression with covariates in the means model and in covariance structure. Maternal, twin-specific, and placental factors were considered as covariates. Heritability of birth weight decreased during gestation from 25 to 42 weeks. However, adjusting for covariates increased the heritability over this time period, with the highest heritability for first-born twins of multipara with separate placentas, who were staying alive (from 52% at 25 weeks to 30% at 42 weeks). Twin-specific factors revealed latent genetic components, whereas placental factors explained common and unique environmental factors. The number of placentas and site of the insertion of the umbilical cord masked the effect of chorionicity. Modeling genetic and environmental factors leads to a better estimate of their role in growth during gestation. For birth weight, mainly environmental factors were explained, resulting in an increase of the heritability and thereby the chance of finding genes influencing birth weight in linkage and association studies.

Human Facial Shape and Size Heritability and Genetic Correlations.

PubMed

Cole, Joanne B; Manyama, Mange; Larson, Jacinda R; Liberton, Denise K; Ferrara, Tracey M; Riccardi, Sheri L; Li, Mao; Mio, Washington; Klein, Ophir D; Santorico, Stephanie A; Hallgrímsson, Benedikt; Spritz, Richard A

2017-02-01

The human face is an array of variable physical features that together make each of us unique and distinguishable. Striking familial facial similarities underscore a genetic component, but little is known of the genes that underlie facial shape differences. Numerous studies have estimated facial shape heritability using various methods. Here, we used advanced three-dimensional imaging technology and quantitative human genetics analysis to estimate narrow-sense heritability, heritability explained by common genetic variation, and pairwise genetic correlations of 38 measures of facial shape and size in normal African Bantu children from Tanzania. Specifically, we fit a linear mixed model of genetic relatedness between close and distant relatives to jointly estimate variance components that correspond to heritability explained by genome-wide common genetic variation and variance explained by uncaptured genetic variation, the sum representing total narrow-sense heritability. Our significant estimates for narrow-sense heritability of specific facial traits range from 28 to 67%, with horizontal measures being slightly more heritable than vertical or depth measures. Furthermore, for over half of facial traits, >90% of narrow-sense heritability can be explained by common genetic variation. We also find high absolute genetic correlation between most traits, indicating large overlap in underlying genetic loci. Not surprisingly, traits measured in the same physical orientation (i.e., both horizontal or both vertical) have high positive genetic correlations, whereas traits in opposite orientations have high negative correlations. The complex genetic architecture of facial shape informs our understanding of the intricate relationships among different facial features as well as overall facial development. Copyright © 2017 by the Genetics Society of America.

Florence Nightingale and the Salisbury incident.

PubMed

Palmer, I S

1976-01-01

Florence Nightingale's astute handling of mismanagement in Free Gifts Stores during the Crimean War underscored her administrative ability. Miss Nightingale went to Scutari ostensibly to nurse the British soldiers, and while there encountered innumerable instances of administrative and managerial ineffectiveness and difficulties. Among these were the problems in the accountability and deployment of supplies as well as the assignment and supervision of female personnel-an untried situation. The article identifies the misdirected organizational management which occasioned the introduction of women into British war nursing and the voluntary participation of the British citizenry in providing supplies and comfort for the Army. Through analysis of Miss Nightingale's and others' private correspondence, the problems of personnel management and supply distribution are brought into sharp focus. The interplay of policies and principles to which Miss Nightingale subscribed, the human frailty of one of her women, Miss Nightingale's illness, and the confusion and stress which characterized the Crimean War are discussed. The compassion, understanding, and rectitude as well as the human values to which Miss Nightingale subscribed in protecting a woman guilty of a breach of trust and felony and the troublesome slanderous attack to which Miss Nightingale was subjected at the instigation of her foes on the home front provide a background for the presentation of the Salisbury affair as an interesting aspect of historical research into the life of the Victorian heroine.

Restoration of HST images with missing data

NASA Technical Reports Server (NTRS)

Adorf, Hans-Martin

1992-01-01

Missing data are a fairly common problem when restoring Hubble Space Telescope observations of extended sources. On Wide Field and Planetary Camera images cosmic ray hits and CCD hot spots are the prevalent causes of data losses, whereas on Faint Object Camera images data are lossed due to reseaux marks, blemishes, areas of saturation and the omnipresent frame edges. This contribution discusses a technique for 'filling in' missing data by statistical inference using information from the surrounding pixels. The major gain consists in minimizing adverse spill-over effects to the restoration in areas neighboring those where data are missing. When the mask delineating the support of 'missing data' is made dynamic, cosmic ray hits, etc. can be detected on the fly during restoration.

Seventh Grade Students' Problem Solving Success Rates on Proportional Reasoning Problems

ERIC Educational Resources Information Center

Pelen, Mustafa Serkan; Artut, Perihan Dinç

2016-01-01

This research was conducted to investigate 7th grade students' problem solving success rates on proportional reasoning problems and whether these success rates change with different problem types. 331 randomly selected students of grade seven participated in this study. A problem test which contains three different types of missing value (direct…

Beneficial effect of a high number of copies of salivary amylase AMY1 gene on obesity risk in Mexican children.

PubMed

Mejía-Benítez, María A; Bonnefond, Amélie; Yengo, Loïc; Huyvaert, Marlène; Dechaume, Aurélie; Peralta-Romero, Jesús; Klünder-Klünder, Miguel; García Mena, Jaime; El-Sayed Moustafa, Julia S; Falchi, Mario; Cruz, Miguel; Froguel, Philippe

2015-02-01

Childhood obesity is a major public health problem in Mexico, affecting one in every three children. Genome-wide association studies identified genetic variants associated with childhood obesity, but a large missing heritability remains to be elucidated. We have recently shown a strong association between a highly polymorphic copy number variant encompassing the salivary amylase gene (AMY1 also known as AMY1A) and obesity in European and Asian adults. In the present study, we aimed to evaluate the association between AMY1 copy number and obesity in Mexican children. We evaluated the number of AMY1 copies in 597 Mexican children (293 obese children and 304 normal weight controls) through highly sensitive digital PCR. The effect of AMY1 copy number on obesity status was assessed using a logistic regression model adjusted for age and sex. We identified a marked effect of AMY1 copy number on reduced risk of obesity (OR per estimated copy 0.84, with the number of copies ranging from one to 16 in this population; p = 4.25 × 10(-6)). The global association between AMY1 copy number and reduced risk of obesity seemed to be mostly driven by the contribution of the highest AMY1 copy number. Strikingly, all children with >10 AMY1 copies were normal weight controls. Salivary amylase initiates the digestion of dietary starch, which is highly consumed in Mexico. Our current study suggests putative benefits of high number of AMY1 copies (and related production of salivary amylase) on energy metabolism in Mexican children.

Genetics of Resistant Hypertension: the Missing Heritability and Opportunities.

PubMed

Teixeira, Samantha K; Pereira, Alexandre C; Krieger, Jose E

2018-05-19

Blood pressure regulation in humans has long been known to be a genetically determined trait. The identification of causal genetic modulators for this trait has been unfulfilling at the least. Despite the recent advances of genome-wide genetic studies, loci associated with hypertension or blood pressure still explain a very low percentage of the overall variation of blood pressure in the general population. This has precluded the translation of discoveries in the genetics of human hypertension to clinical use. Here, we propose the combined use of resistant hypertension as a trait for mapping genetic determinants in humans and the integration of new large-scale technologies to approach in model systems the multidimensional nature of the problem. New large-scale efforts in the genetic and genomic arenas are paving the way for an increased and granular understanding of genetic determinants of hypertension. New technologies for whole genome sequence and large-scale forward genetic screens can help prioritize gene and gene-pathways for downstream characterization and large-scale population studies, and guided pharmacological design can be used to drive discoveries to the translational application through better risk stratification and new therapeutic approaches. Although significant challenges remain in the mapping and identification of genetic determinants of hypertension, new large-scale technological approaches have been proposed to surpass some of the shortcomings that have limited progress in the area for the last three decades. The incorporation of these technologies to hypertension research may significantly help in the understanding of inter-individual blood pressure variation and the deployment of new phenotyping and treatment approaches for the condition.

Genetic effects on beef tenderness in Bos indicus composite and Bos taurus cattle.

PubMed

O'Connor, S F; Tatum, J D; Wulf, D M; Green, R D; Smith, G C

1997-07-01

Bos indicus composite and Bos taurus cattle, originating from diverse production environments, were used to quantify genetic variation in marbling, 24-h calpastatin activity, and beef tenderness and to identify strategies for prevention of beef tenderness problems in Bos indicus composite cattle. Comparisons among 3/8 Bos indicus breeds (Braford, Red Brangus, Simbrah) revealed significant differences in marbling and 24-h calpastatin activity, but not in tenderness. Compared with Bos taurus cattle, 3/ 8 Bos indicus cattle had similar marbling scores but higher 24-h calpastatin activities. Also, beef from 3/8 Bos indicus composites aged more slowly from 1 to 7 d and was less tender at 4, 7, 14, 21, and 35 d postmortem than beef from Bos taurus cattle. However, beef from 3/8 Bos indicus cattle was relatively tender if it was aged for a sufficient period of time (21 d). The delayed response to aging and greater toughness of beef from 3/8 Bos indicus cattle was associated with Brahman breed effects and was not related to the Bos taurus germplasm source. Marbling was moderately heritable (.52 +/- .21) but exhibited positive genetic correlations with shear force at d 1 through 14 of aging, suggesting that, in these cattle, selection for increased marbling would have an unfavorable effect on beef tenderness. A low heritability estimate for 24-h calpastatin activity (.15 +/- .15), coupled with low genetic correlations between calpastatin activity and shear force at 7, 14, and 35 d, suggested that selection for low calpastatin activity would have little effect on aged beef tenderness. Panel tenderness and shear force at 7, 14, and 21 d were moderately heritable (.27 to .47), indicating that aged beef tenderness could be improved by direct selection (via progeny testing). Comparisons among Simbrah, Senegus x Simbrah, and Red Angus x Simmental steers showed that inclusion of a tropically adapted Bos taurus breed (Senepol) could be an effective strategy for preventing beef tenderness problems in heat-tolerant cattle.

Reconstructing missing daily precipitation data using regression trees and artificial neural networks

USDA-ARS?s Scientific Manuscript database

Incomplete meteorological data has been a problem in environmental modeling studies. The objective of this work was to develop a technique to reconstruct missing daily precipitation data in the central part of Chesapeake Bay Watershed using regression trees (RT) and artificial neural networks (ANN)....

Genetics of wellbeing and its components satisfaction with life, happiness, and quality of life: a review and meta-analysis of heritability studies.

PubMed

Bartels, Meike

2015-03-01

Wellbeing is a major topic of research across several disciplines, reflecting the increasing recognition of its strong value across major domains in life. Previous twin-family studies have revealed that individual differences in wellbeing are accounted for by both genetic as well as environmental factors. A systematic literature search identified 30 twin-family studies on wellbeing or a related measure such as satisfaction with life or happiness. Review of these studies showed considerable variation in heritability estimates (ranging from 0 to 64 %), which makes it difficult to draw firm conclusions regarding the genetic influences on wellbeing. For overall wellbeing twelve heritability estimates, from 10 independent studies, were meta-analyzed by computing a sample size weighted average heritability. Ten heritability estimates, derived from 9 independent samples, were used for the meta-analysis of satisfaction with life. The weighted average heritability of wellbeing, based on a sample size of 55,974 individuals, was 36 % (34-38), while the weighted average heritability for satisfaction with life was 32 % (29-35) (n = 47,750). With this result a more robust estimate of the relative influence of genetic effects on wellbeing is provided.

Evolutionary potential of upper thermal tolerance: biogeographic patterns and expectations under climate change.

PubMed

Diamond, Sarah E

2017-02-01

How will organisms respond to climate change? The rapid changes in global climate are expected to impose strong directional selection on fitness-related traits. A major open question then is the potential for adaptive evolutionary change under these shifting climates. At the most basic level, evolutionary change requires the presence of heritable variation and natural selection. Because organismal tolerances of high temperature place an upper bound on responding to temperature change, there has been a surge of research effort on the evolutionary potential of upper thermal tolerance traits. Here, I review the available evidence on heritable variation in upper thermal tolerance traits, adopting a biogeographic perspective to understand how heritability of tolerance varies across space. Specifically, I use meta-analytical models to explore the relationship between upper thermal tolerance heritability and environmental variability in temperature. I also explore how variation in the methods used to obtain these thermal tolerance heritabilities influences the estimation of heritable variation in tolerance. I conclude by discussing the implications of a positive relationship between thermal tolerance heritability and environmental variability in temperature and how this might influence responses to future changes in climate. © 2016 New York Academy of Sciences.

Treatment of missing data in follow-up studies of randomised controlled trials: A systematic review of the literature.

PubMed

Sullivan, Thomas R; Yelland, Lisa N; Lee, Katherine J; Ryan, Philip; Salter, Amy B

2017-08-01

After completion of a randomised controlled trial, an extended follow-up period may be initiated to learn about longer term impacts of the intervention. Since extended follow-up studies often involve additional eligibility restrictions and consent processes for participation, and a longer duration of follow-up entails a greater risk of participant attrition, missing data can be a considerable threat in this setting. As a potential source of bias, it is critical that missing data are appropriately handled in the statistical analysis, yet little is known about the treatment of missing data in extended follow-up studies. The aims of this review were to summarise the extent of missing data in extended follow-up studies and the use of statistical approaches to address this potentially serious problem. We performed a systematic literature search in PubMed to identify extended follow-up studies published from January to June 2015. Studies were eligible for inclusion if the original randomised controlled trial results were also published and if the main objective of extended follow-up was to compare the original randomised groups. We recorded information on the extent of missing data and the approach used to treat missing data in the statistical analysis of the primary outcome of the extended follow-up study. Of the 81 studies included in the review, 36 (44%) reported additional eligibility restrictions and 24 (30%) consent processes for entry into extended follow-up. Data were collected at a median of 7 years after randomisation. Excluding 28 studies with a time to event primary outcome, 51/53 studies (96%) reported missing data on the primary outcome. The median percentage of randomised participants with complete data on the primary outcome was just 66% in these studies. The most common statistical approach to address missing data was complete case analysis (51% of studies), while likelihood-based analyses were also well represented (25%). Sensitivity analyses around the missing data mechanism were rarely performed (25% of studies), and when they were, they often involved unrealistic assumptions about the mechanism. Despite missing data being a serious problem in extended follow-up studies, statistical approaches to addressing missing data were often inadequate. We recommend researchers clearly specify all sources of missing data in follow-up studies and use statistical methods that are valid under a plausible assumption about the missing data mechanism. Sensitivity analyses should also be undertaken to assess the robustness of findings to assumptions about the missing data mechanism.

VIGAN: Missing View Imputation with Generative Adversarial Networks.

PubMed

Shang, Chao; Palmer, Aaron; Sun, Jiangwen; Chen, Ko-Shin; Lu, Jin; Bi, Jinbo

2017-01-01

In an era when big data are becoming the norm, there is less concern with the quantity but more with the quality and completeness of the data. In many disciplines, data are collected from heterogeneous sources, resulting in multi-view or multi-modal datasets. The missing data problem has been challenging to address in multi-view data analysis. Especially, when certain samples miss an entire view of data, it creates the missing view problem. Classic multiple imputations or matrix completion methods are hardly effective here when no information can be based on in the specific view to impute data for such samples. The commonly-used simple method of removing samples with a missing view can dramatically reduce sample size, thus diminishing the statistical power of a subsequent analysis. In this paper, we propose a novel approach for view imputation via generative adversarial networks (GANs), which we name by VIGAN. This approach first treats each view as a separate domain and identifies domain-to-domain mappings via a GAN using randomly-sampled data from each view, and then employs a multi-modal denoising autoencoder (DAE) to reconstruct the missing view from the GAN outputs based on paired data across the views. Then, by optimizing the GAN and DAE jointly, our model enables the knowledge integration for domain mappings and view correspondences to effectively recover the missing view. Empirical results on benchmark datasets validate the VIGAN approach by comparing against the state of the art. The evaluation of VIGAN in a genetic study of substance use disorders further proves the effectiveness and usability of this approach in life science.

Progression of lumbar disc degeneration over a decade: a heritability study

PubMed Central

Williams, Frances M K; Popham, Maria; Sambrook, Philip N; Jones, Annette F; Spector, Tim D; MacGregor, Alex J

2011-01-01

Objectives Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Cross-sectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors. Methods A 10-year follow-up of MRI-determined LDD was performed in 234 pairs of twin volunteers in the UK and Australia, comprising 90 monozygotic pairs and 144 dizygotic same-sex twin pairs. Of the total sample, 95% were female. The mean age at baseline was 53.3 years (range 32.3–69.5). The rate of progression was calculated and, because the effect of age was non-linear, the sample was divided into age strata and heritability estimated for each trait's progression. Results All MRI-determined traits worsened significantly over the period of follow-up (p<0.0001 for each). Change in disc height was not heritable at any age while posterior disc bulge was heritable across all age categories (range 28–53%), with higher heritability in those over 60 years. Change in disc signal intensity and anterior osteophytes were found to be heritable only in those aged under 50 years at baseline (heritability estimates 76% (95% CI 44% to 100%) and 74% (42% to 100%), respectively). Conclusions Longitudinal change in LDD traits is heritable for all traits except disc height, but there is a significant influence of age, which varies across traits. Future studies to define the genetic variants influencing LDD progression should examine MRI traits individually and in women should focus on those under 50 years of age. PMID:21402564

Heritability of Neuropsychological Measures in Schizophrenia and Nonpsychiatric Populations: A Systematic Review and Meta-analysis.

PubMed

Blokland, Gabriëlla A M; Mesholam-Gately, Raquelle I; Toulopoulou, Timothea; Del Re, Elisabetta C; Lam, Max; DeLisi, Lynn E; Donohoe, Gary; Walters, James T R; Seidman, Larry J; Petryshen, Tracey L

2017-07-01

Schizophrenia is characterized by neuropsychological deficits across many cognitive domains. Cognitive phenotypes with high heritability and genetic overlap with schizophrenia liability can help elucidate the mechanisms leading from genes to psychopathology. We performed a meta-analysis of 170 published twin and family heritability studies of >800 000 nonpsychiatric and schizophrenia subjects to accurately estimate heritability across many neuropsychological tests and cognitive domains. The proportion of total variance of each phenotype due to additive genetic effects (A), shared environment (C), and unshared environment and error (E), was calculated by averaging A, C, and E estimates across studies and weighting by sample size. Heritability ranged across phenotypes, likely due to differences in genetic and environmental effects, with the highest heritability for General Cognitive Ability (32%-67%), Verbal Ability (43%-72%), Visuospatial Ability (20%-80%), and Attention/Processing Speed (28%-74%), while the lowest heritability was observed for Executive Function (20%-40%). These results confirm that many cognitive phenotypes are under strong genetic influences. Heritability estimates were comparable in nonpsychiatric and schizophrenia samples, suggesting that environmental factors and illness-related moderators (eg, medication) do not substantially decrease heritability in schizophrenia samples, and that genetic studies in schizophrenia samples are informative for elucidating the genetic basis of cognitive deficits. Substantial genetic overlap between cognitive phenotypes and schizophrenia liability (average rg = -.58) in twin studies supports partially shared genetic etiology. It will be important to conduct comparative studies in well-powered samples to determine whether the same or different genes and genetic variants influence cognition in schizophrenia patients and the general population. © The Author 2016. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Heritability of Blood Pressure Responses to Dietary Sodium and Potassium Intake in Chinese Population

PubMed Central

Gu, Dongfeng; Rice, Treva; Wang, Shiping; Yang, Wenjie; Gu, Chi; Chen, Chung-Shiuan; Hixson, James E.; Jaquish, Cashell E.; Yao, Zhi-Jian; Liu, De-Pei; Rao, Dabeeru C.; He, Jiang

2008-01-01

The heritability of blood pressure responses to dietary intervention has not been well studied. We examined the heritability of blood pressure responses to dietary sodium and potassium intake in a family feeding-study among 1,906 study participants living in rural north China. The dietary intervention included a 7-day low sodium-feeding (51.3 mmol/day), a 7-day high sodium-feeding (307.8 mmol/day), and a 7-day high-sodium plus potassium-supplementation (60 mmol/day). Blood pressure was measured 9 times during the 3-day baseline period preceding the intervention and also during the last 3 days of each intervention phase using a random-zero sphygmomanometer. Heritability was computed using maximum likelihood methods under a variance components model as implemented in the computer program SOLAR. The heritabilities of baseline blood pressure were 0.31 for systolic, 0.32 for diastolic, and 0.34 for mean arterial pressure. The heritabilities increased significantly under dietary intervention and were 0.49, 0.49, and 0.51 during low-sodium, 0.47, 0.49, and 0.51 during high-sodium, and 0.51, 0.52, and 0.53 during potassium-supplementation for systolic, diastolic, and mean arterial pressure, respectively. The heritabilities for percentage blood pressure responses to low-sodium were 0.20, 0.21 and 0.23, to high-sodium were 0.22, 0.33, and 0.33, and to potassium-supplementation were 0.24, 0.21, and 0.25, for systolic, diastolic, and mean arterial pressure, respectively. Our study indicated that the heritabilities of blood pressure under controlled dietary sodium and potassium intake were significantly higher than those under usual diet. In addition, the heritabilities of blood pressure responses to dietary sodium and potassium intake were moderate in this study population. PMID:17485599

Order-restricted inference for means with missing values.

PubMed

Wang, Heng; Zhong, Ping-Shou

2017-09-01

Missing values appear very often in many applications, but the problem of missing values has not received much attention in testing order-restricted alternatives. Under the missing at random (MAR) assumption, we impute the missing values nonparametrically using kernel regression. For data with imputation, the classical likelihood ratio test designed for testing the order-restricted means is no longer applicable since the likelihood does not exist. This article proposes a novel method for constructing test statistics for assessing means with an increasing order or a decreasing order based on jackknife empirical likelihood (JEL) ratio. It is shown that the JEL ratio statistic evaluated under the null hypothesis converges to a chi-bar-square distribution, whose weights depend on missing probabilities and nonparametric imputation. Simulation study shows that the proposed test performs well under various missing scenarios and is robust for normally and nonnormally distributed data. The proposed method is applied to an Alzheimer's disease neuroimaging initiative data set for finding a biomarker for the diagnosis of the Alzheimer's disease. © 2017, The International Biometric Society.

Spacecraft intercept guidance using zero effort miss steering

NASA Astrophysics Data System (ADS)

Newman, Brett

The suitability of proportional navigation, or an equivalent zero effort miss formulation, for spacecraft intercepts during midcourse guidance, followed by a ballistic coast to the endgame, is addressed. The problem is formulated in terms of relative motion in a general 3D framework. The proposed guidance law for the commanded thrust vector orientation consists of the sum of two terms: (1) along the line of sight unit direction and (2) along the zero effort miss component perpendicular to the line of sight and proportional to the miss itself and a guidance gain. If the guidance law is to be suitable for longer range targeting applications with significant ballistic coasting after burnout, determination of the zero effort miss must account for the different gravitational accelerations experienced by each vehicle. The proposed miss determination techniques employ approximations for the true differential gravity effect. Theoretical results are applied to a numerical engagement scenario and the resulting performance is evaluated in terms of the miss distances determined from nonlinear simulation.

Independence of heritable influences on the food intake of free-living humans.

PubMed

de Castro, John M

2002-01-01

The time of day of meal ingestion, the number of people present at the meal, the subjective state of hunger, and the estimated before-meal contents in the stomach have been established as influences on the amount eaten in a meal and these influences have been shown to be heritable. Because these factors intercorrelate, the calculated heritabilities for some of these variables might result indirectly from their covariation with one of the other heritable variables. The independence of the heritability of the influence of these four factors was investigated with 110 identical and 102 fraternal same-sex and 53 fraternal mixed-sex adult twin pairs who were paid to maintain 7-d food-intake diaries. From the diary reports, the meal sizes were calculated and subjected to multiple regression analysis using the estimated before-meal stomach contents, the reported number of other people present, the subjective hunger ratings, and the time of day of the meal as predictors. Linear structural modeling was applied to the beta-coefficients from the multiple regression to investigate whether the heritability of the influences of these four variables was independent. Significant genetic effects were found for the beta-coefficients for all four variables, indicating that the heritability of their relationship with intake is to some extent independent and heritable. This suggests that influences of multiple factors on intake are influenced by the genes and become part of the total package of genetically determined physiologic, sociocultural, and psychological processes that regulate energy balance.

Heritability of diurnal changes in food intake in free-living humans.

PubMed

de Castro, J M

2001-09-01

The time of day of meal ingestion, the number of people present at the meal, the subjective state of hunger, and the estimated before-meal contents in the stomach have been established as influences on the amount eaten in a meal, and this influence has been shown to be heritable. Because these factors intercorrelate, the possibility that the calculated heritabilities for some of these variables could result indirectly from their convariation with one of the other heritable variables was assessed. The independence of the heritability of the influence of these four factors was investigated with 110 identical and 102 fraternal same-sex and 53 fraternal mixed-sex adult twin pairs who were paid to maintain 7-d food intake diaries. From the diary reports, the meal sizes were calculated and subjected to multiple regression analysis using the estimated before-meal stomach contents, the reported number of other people present, the subjective hunger ratings, and the time of day of the meal as predictors. Linear structural modeling was applied to the beta coefficients from the multiple regression to investigate whether the heritability of the influences of these four variables was independent. Significant genetic effects were found for the beta coefficients for all four variables, indicating that the heritability of their relationship with intake is to some extent heritable. These results suggest that the influences of multiple factors on intake are influenced by the genes and become part of the total package of genetically determined physiologic, sociocultural, and psychological processes that regulate energy balance.

Heritability estimates of the Big Five personality traits based on common genetic variants.

PubMed

Power, R A; Pluess, M

2015-07-14

According to twin studies, the Big Five personality traits have substantial heritable components explaining 40-60% of the variance, but identification of associated genetic variants has remained elusive. Consequently, knowledge regarding the molecular genetic architecture of personality and to what extent it is shared across the different personality traits is limited. Using genomic-relatedness-matrix residual maximum likelihood analysis (GREML), we here estimated the heritability of the Big Five personality factors (extraversion, agreeableness, conscientiousness, neuroticism and openness for experience) in a sample of 5011 European adults from 527,469 single-nucleotide polymorphisms across the genome. We tested for the heritability of each personality trait, as well as for the genetic overlap between the personality factors. We found significant and substantial heritability estimates for neuroticism (15%, s.e. = 0.08, P = 0.04) and openness (21%, s.e. = 0.08, P < 0.01), but not for extraversion, agreeableness and conscientiousness. The bivariate analyses showed that the variance explained by common variants entirely overlapped between neuroticism and openness (rG = 1.00, P < 0.001), despite low phenotypic correlation (r = - 0.09, P < 0.001), suggesting that the remaining unique heritability may be determined by rare or structural variants. As far as we are aware of, this is the first study estimating the shared and unique heritability of all Big Five personality traits using the GREML approach. Findings should be considered exploratory and suggest that detectable heritability estimates based on common variants is shared between neuroticism and openness to experiences.

Ontogenetic variation of heritability and maternal effects in yellow-bellied marmot alarm calls.

PubMed

Blumstein, Daniel T; Nguyen, Kathy T; Martin, Julien G A

2013-05-07

Individuals of many species produce distinctive vocalizations that may relay potential information about the signaller. The alarm calls of some species have been reported to be individually specific, and this distinctiveness may allow individuals to access the reliability or kinship of callers. While not much is known generally about the heritability of mammalian vocalizations, if alarm calls were individually distinctive to permit kinship assessment, then call structure should be heritable. Here, we show conclusively for the first time that alarm call structure is heritable. We studied yellow-bellied marmots (Marmota flaviventris) and made nine quantitative measurements of their alarm calls. With a known genealogy, we used the animal model (a statistical technique) to estimate alarm call heritability. In juveniles, only one of the measured variables had heritability significantly different from zero; however, most variables had significant maternal environmental effects. By contrast, yearlings and adults had no significant maternal environmental effects, but the heritability of nearly all measured variables was significantly different from zero. Some, but not all of these heritable effects were significantly different across age classes. The presence of significantly non-zero maternal environmental effects in juveniles could reflect the impact of maternal environmental stresses on call structure. Regardless of this mechanism, maternal environmental effects could permit kinship recognition in juveniles. In older animals, the substantial genetic basis of alarm call structure suggests that calls could be used to assess kinship and, paradoxically, might also suggest a role of learning in call structure.

Ontogenetic variation of heritability and maternal effects in yellow-bellied marmot alarm calls

PubMed Central

Blumstein, Daniel T.; Nguyen, Kathy T.; Martin, Julien G. A.

2013-01-01

Individuals of many species produce distinctive vocalizations that may relay potential information about the signaller. The alarm calls of some species have been reported to be individually specific, and this distinctiveness may allow individuals to access the reliability or kinship of callers. While not much is known generally about the heritability of mammalian vocalizations, if alarm calls were individually distinctive to permit kinship assessment, then call structure should be heritable. Here, we show conclusively for the first time that alarm call structure is heritable. We studied yellow-bellied marmots (Marmota flaviventris) and made nine quantitative measurements of their alarm calls. With a known genealogy, we used the animal model (a statistical technique) to estimate alarm call heritability. In juveniles, only one of the measured variables had heritability significantly different from zero; however, most variables had significant maternal environmental effects. By contrast, yearlings and adults had no significant maternal environmental effects, but the heritability of nearly all measured variables was significantly different from zero. Some, but not all of these heritable effects were significantly different across age classes. The presence of significantly non-zero maternal environmental effects in juveniles could reflect the impact of maternal environmental stresses on call structure. Regardless of this mechanism, maternal environmental effects could permit kinship recognition in juveniles. In older animals, the substantial genetic basis of alarm call structure suggests that calls could be used to assess kinship and, paradoxically, might also suggest a role of learning in call structure. PMID:23466987

Reducing Missed Laboratory Results: Defining Temporal Responsibility, Generating User Interfaces for Test Process Tracking, and Retrospective Analyses to Identify Problems

PubMed Central

Tarkan, Sureyya; Plaisant, Catherine; Shneiderman, Ben; Hettinger, A. Zachary

2011-01-01

Researchers have conducted numerous case studies reporting the details on how laboratory test results of patients were missed by the ordering medical providers. Given the importance of timely test results in an outpatient setting, there is limited discussion of electronic versions of test result management tools to help clinicians and medical staff with this complex process. This paper presents three ideas to reduce missed results with a system that facilitates tracking laboratory tests from order to completion as well as during follow-up: (1) define a workflow management model that clarifies responsible agents and associated time frame, (2) generate a user interface for tracking that could eventually be integrated into current electronic health record (EHR) systems, (3) help identify common problems in past orders through retrospective analyses. PMID:22195201

Comparison of Modern Methods for Analyzing Repeated Measures Data with Missing Values

ERIC Educational Resources Information Center

Vallejo, G.; Fernandez, M. P.; Livacic-Rojas, P. E.; Tuero-Herrero, E.

2011-01-01

Missing data are a pervasive problem in many psychological applications in the real world. In this article we study the impact of dropout on the operational characteristics of several approaches that can be easily implemented with commercially available software. These approaches include the covariance pattern model based on an unstructured…

Solutions for Missing Data in Structural Equation Modeling

ERIC Educational Resources Information Center

Carter, Rufus Lynn

2006-01-01

Many times in both educational and social science research it is impossible to collect data that is complete. When administering a survey, for example, people may answer some questions and not others. This missing data causes a problem for researchers using structural equation modeling (SEM) techniques for data analyses. Because SEM and…

Use of Missing Data Methods in Longitudinal Studies: The Persistence of Bad Practices in Developmental Psychology

ERIC Educational Resources Information Center

Jelicic, Helena; Phelps, Erin; Lerner, Richard M.

2009-01-01

Developmental science rests on describing, explaining, and optimizing intraindividual changes and, hence, empirically requires longitudinal research. Problems of missing data arise in most longitudinal studies, thus creating challenges for interpreting the substance and structure of intraindividual change. Using a sample of reports of longitudinal…

Principle Component Analysis with Incomplete Data: A simulation of R pcaMethods package in Constructing an Environmental Quality Index with Missing Data

EPA Science Inventory

Missing data is a common problem in the application of statistical techniques. In principal component analysis (PCA), a technique for dimensionality reduction, incomplete data points are either discarded or imputed using interpolation methods. Such approaches are less valid when ...

Least-Squares Approximation of an Improper Correlation Matrix by a Proper One.

ERIC Educational Resources Information Center

Knol, Dirk L.; ten Berge, Jos M. F.

1989-01-01

An algorithm, based on a solution for C. I. Mosier's oblique Procrustes rotation problem, is presented for the best least-squares fitting correlation matrix approximating a given missing value or improper correlation matrix. Results are of interest for missing value and tetrachoric correlation, indefinite matrix correlation, and constrained…

Low Cognitive Functioning in Nondemented 80+-Year-Old Twins Is Not Heritable.

ERIC Educational Resources Information Center

Petrill, Stephen A.; Johansson, Boo; Pedersen, Nancy L.; Berg, Stig; Plomin, Robert; Ahern, Frank; McClearn, Gerald E.

2001-01-01

Studied the genetic influence of low cognitive functioning in 200 pairs of twins aged at least 80 years and identified as not demented. Results suggest that the heritability of low cognitive functioning in this group was nonsignificant, but above-average cognitive functioning shows substantial group heritability. (SLD)

75 FR 46947 - Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-04

..., guidelines and programs for effectively reducing morbidity and mortality in newborns and children having or... Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting In accordance with... following meeting: Name: Secretary's Advisory Committee on Heritable Disorders in Newborns and Children...

Genetic and Phenotypic Parameter Estimates for Feed Intake and Other Traits in Growing Beef Cattle

USDA-ARS?s Scientific Manuscript database

Intake and feed efficiency were moderately heritable; however, residual feed intake was more heritable than intake and feed efficiency. Adjusting residual feed intake and feed efficiency for carcass fatness had little effect on heritability and correlations with remaining traits. Flight speed was ...

Laboratory Estimates of Heritabilities and Genetic Correlations in Nature

PubMed Central

Riska, B.; Prout, T.; Turelli, M.

1989-01-01

A lower bound on heritability in a natural environment can be determined from the regression of offspring raised in the laboratory on parents raised in nature. An estimate of additive genetic variance in the laboratory is also required. The estimated lower bounds on heritabilities can sometimes be used to demonstrate a significant genetic correlation between two traits in nature, if their genetic and phenotypic correlations in nature have the same sign, and if sample sizes are large, and heritabilities and phenotypic and genetic correlations are high. PMID:2515111

Heritability and familiality of neurological soft signs: evidence from healthy twins, patients with schizophrenia and non-psychotic first-degree relatives.

PubMed

Xu, T; Wang, Y; Li, Z; Huang, J; Lui, S S Y; Tan, S-P; Yu, X; Cheung, E F C; He, M-G; Ott, J; Gur, R E; Gur, R C; Chan, R C K

2016-01-01

Neurological soft signs (NSS) have long been considered potential endophenotypes for schizophrenia. However, few studies have investigated the heritability and familiality of NSS. The present study examined the heritability and familiality of NSS in healthy twins and patient-relative pairs. The abridged version of the Cambridge Neurological Inventory was administered to 267 pairs of monozygotic twins, 124 pairs of dizygotic twins, and 75 pairs of patients with schizophrenia and their non-psychotic first-degree relatives. NSS were found to have moderate but significant heritability in the healthy twin sample. Moreover, patients with schizophrenia correlated closely with their first-degree relatives on NSS. Taken together, the findings provide evidence on the heritability and familiality of NSS in the Han Chinese population.

Screening and treatment for heritable thrombophilia in pregnancy failure: inconsistencies among UK early pregnancy units.

PubMed

Norrie, Gillian; Farquharson, Roy G; Greaves, Mike

2009-01-01

The significance of heritable thrombophilia in pregnancy failure is controversial. We surveyed all UK Early Pregnancy Units and 70% responded. The majority test routinely for heritable thrombophilias; 80%, 76% and 88% undertook at least one screening test in late miscarriage, recurrent miscarriage and placental abruption, respectively. The range of thrombophilias sought is inconsistent: testing for proteins C and S deficiency and F5 R506Q (factor V Leiden) is most prevalent. Detection of heritable thrombophilia frequently leads to administration of antithrombotics in subsequent pregnancies. Thus, thrombophilia testing and use of antithrombotics are widespread in the UK despite controversies regarding the role of heritable thrombophilia in the pathogenesis of pregnancy complications, and the lack of robust evidence for the efficacy of antithrombotic therapy.

Heritability of antisocial behaviour at 9: do callous-unemotional traits matter?

PubMed

Viding, Essi; Jones, Alice P; Frick, Paul J; Moffitt, Terrie E; Plomin, Robert

2008-01-01

A previous finding from our group indicated that teacher-rated antisocial behaviour (AB) among 7-year-olds is particularly heritable in the presence of callous-unemotional (CU) traits. Using a sample of 1865 same-sex twin pairs, we employed DeFries-Fulker extremes analysis to investigate whether teacher-rated AB with/without CU traits also shows aetiological differences among 9-year-olds. Furthermore, we assessed whether the differences in the magnitude of heritability would be evident even when hyperactive symptoms were controlled for in the statistical analysis. AB among 9-year-olds was more heritable with than without concomitant CU. The heritability difference was even more pronounced in magnitude when hyperactive symptoms were controlled. CU traits thus appear to index one valid way of sub-typing children with early-onset AB.

Heritability of vaccine-induced measles neutralizing antibody titers.

PubMed

Schaid, Daniel J; Haralambieva, Iana H; Larrabee, Beth R; Ovsyannikova, Inna G; Kennedy, Richard B; Poland, Gregory A

2017-03-07

Understanding how genetics influences inter-individual variation of antibody titers in response to measles vaccination is vital to understanding possible sources of vaccine failure as well as improved vaccine development. Although it is recognized that both the human leukocyte antigen (HLA) genes and the immunoglobulin allotype genes play significant roles in immune response, there is significant variation in antibody titers that is not explained by these genes. To obtain a more complete estimate of the role of the entire genome, we used a large panel of single nucleotide polymorphisms to estimate the heritability of antibody response to measles vaccine. Based on 935 subjects with European ancestry, we estimated the heritability to be 49% (standard error 0.17). We also estimated the heritability attributable to each chromosome, and found a large range in chromosome-specific heritabilities. Notably, chromosome 1 had the largest estimate (28%), while chromosome 6, which harbors HLA, had an estimated heritability of 13%. Compared with a prior study of twins in the same community, which resulted in a heritability estimate of 88.5%, our study suggests there are either many rare genetic variants, or many common genetic variants of small effect sizes that contribute to variations of antibody titers in response to measles vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.

The heritability of avoidant and dependent personality disorder assessed by personal interview and questionnaire.

PubMed

Gjerde, L C; Czajkowski, N; Røysamb, E; Orstavik, R E; Knudsen, G P; Ostby, K; Torgersen, S; Myers, J; Kendler, K S; Reichborn-Kjennerud, T

2012-12-01

Personality disorders (PDs) have been shown to be modestly heritable. Accurate heritability estimates are, however, dependent on reliable measurement methods, as measurement error deflates heritability. The aim of this study was to estimate the heritability of DSM-IV avoidant and dependent personality disorder, by including two measures of the PDs at two time points. Data were obtained from a population-based cohort of young adult Norwegian twins, of whom 8045 had completed a self-report questionnaire assessing PD traits. 2794 of these twins subsequently underwent a structured diagnostic interview for DSM-IV PDs. Questionnaire items predicting interview results were selected by multiple regression, and measurement models of the PDs were fitted in Mx. The heritabilities of the PD factors were 0.64 for avoidant PD and 0.66 for dependent PD. No evidence of common environment, that is, environmental factors that are shared between twins and make them similar, was found. Genetic and environmental contributions to avoidant and dependent PD seemed to be the same across sexes. The combination of both a questionnaire- and an interview assessment of avoidant and dependent PD results in substantially higher heritabilities than previously found using single-occasion interviews only. © 2012 John Wiley & Sons A/S.

Heritabilities of Facial Measurements and Their Latent Factors in Korean Families

PubMed Central

Kim, Hyun-Jin; Im, Sun-Wha; Jargal, Ganchimeg; Lee, Siwoo; Yi, Jae-Hyuk; Park, Jeong-Yeon; Sung, Joohon; Cho, Sung-Il; Kim, Jong-Yeol; Kim, Jong-Il; Seo, Jeong-Sun

2013-01-01

Genetic studies on facial morphology targeting healthy populations are fundamental in understanding the specific genetic influences involved; yet, most studies to date, if not all, have been focused on congenital diseases accompanied by facial anomalies. To study the specific genetic cues determining facial morphology, we estimated familial correlations and heritabilities of 14 facial measurements and 3 latent factors inferred from a factor analysis in a subset of the Korean population. The study included a total of 229 individuals from 38 families. We evaluated a total of 14 facial measurements using 2D digital photographs. We performed factor analysis to infer common latent variables. The heritabilities of 13 facial measurements were statistically significant (p < 0.05) and ranged from 0.25 to 0.61. Of these, the heritability of intercanthal width in the orbital region was found to be the highest (h2 = 0.61, SE = 0.14). Three factors (lower face portion, orbital region, and vertical length) were obtained through factor analysis, where the heritability values ranged from 0.45 to 0.55. The heritability values for each factor were higher than the mean heritability value of individual original measurements. We have confirmed the genetic influence on facial anthropometric traits and suggest a potential way to categorize and analyze the facial portions into different groups. PMID:23843774

Growth Problems

MedlinePlus

... hormones needed to grow and develop. For example, Turner syndrome is a genetic condition (due to a problem ... a missing or abnormal X chromosome. Girls with Turner syndrome tend to be short and don't usually ...

Reconstructing (super)trees from data sets with missing distances: not all is lost.

PubMed

Kettleborough, George; Dicks, Jo; Roberts, Ian N; Huber, Katharina T

2015-06-01

The wealth of phylogenetic information accumulated over many decades of biological research, coupled with recent technological advances in molecular sequence generation, presents significant opportunities for researchers to investigate relationships across and within the kingdoms of life. However, to make best use of this data wealth, several problems must first be overcome. One key problem is finding effective strategies to deal with missing data. Here, we introduce Lasso, a novel heuristic approach for reconstructing rooted phylogenetic trees from distance matrices with missing values, for data sets where a molecular clock may be assumed. Contrary to other phylogenetic methods on partial data sets, Lasso possesses desirable properties such as its reconstructed trees being both unique and edge-weighted. These properties are achieved by Lasso restricting its leaf set to a large subset of all possible taxa, which in many practical situations is the entire taxa set. Furthermore, the Lasso approach is distance-based, rendering it very fast to run and suitable for data sets of all sizes, including large data sets such as those generated by modern Next Generation Sequencing technologies. To better understand the performance of Lasso, we assessed it by means of artificial and real biological data sets, showing its effectiveness in the presence of missing data. Furthermore, by formulating the supermatrix problem as a particular case of the missing data problem, we assessed Lasso's ability to reconstruct supertrees. We demonstrate that, although not specifically designed for such a purpose, Lasso performs better than or comparably with five leading supertree algorithms on a challenging biological data set. Finally, we make freely available a software implementation of Lasso so that researchers may, for the first time, perform both rooted tree and supertree reconstruction with branch lengths on their own partial data sets. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Mind the Gap: The Prospects of Missing Data.

PubMed

McConnell, Meghan; Sherbino, Jonathan; Chan, Teresa M

2016-12-01

The increasing use of workplace-based assessments (WBAs) in competency-based medical education has led to large data sets that assess resident performance longitudinally. With large data sets, problems that arise from missing data are increasingly likely. The purpose of this study is to examine (1) whether data are missing at random across various WBAs, and (2) the relationship between resident performance and the proportion of missing data. During 2012-2013, a total of 844 WBAs of CanMEDs Roles were completed for 9 second-year emergency medicine residents. To identify whether missing data were randomly distributed across various WBAs, the total number of missing data points was calculated for each Role. To examine whether the amount of missing data was related to resident performance, 5 faculty members rank-ordered the residents based on performance. A median rank score was calculated for each resident and was correlated with the proportion of missing data. More data were missing for Health Advocate and Professional WBAs relative to other competencies ( P  < .001). Furthermore, resident rankings were not related to the proportion of missing data points ( r  = 0.29, P  > .05). The results of the present study illustrate that some CanMEDS Roles are less likely to be assessed than others. At the same time, the amount of missing data did not correlate with resident performance, suggesting lower-performing residents are no more likely to have missing data than their higher-performing peers. This article discusses several approaches to dealing with missing data.

Systematic Prioritization and Integrative Analysis of Copy Number Variations in Schizophrenia Reveal Key Schizophrenia Susceptibility Genes

PubMed Central

Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

2014-01-01

Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and diagnostics. PMID:24664977

Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity.

PubMed

Pigeyre, Marie; Yazdi, Fereshteh T; Kaur, Yuvreet; Meyre, David

2016-06-01

In high-, middle- and low-income countries, the rising prevalence of obesity is the underlying cause of numerous health complications and increased mortality. Being a complex and heritable disorder, obesity results from the interplay between genetic susceptibility, epigenetics, metagenomics and the environment. Attempts at understanding the genetic basis of obesity have identified numerous genes associated with syndromic monogenic, non-syndromic monogenic, oligogenic and polygenic obesity. The genetics of leanness are also considered relevant as it mirrors some of obesity's aetiologies. In this report, we summarize ten genetically elucidated obesity syndromes, some of which are involved in ciliary functioning. We comprehensively review 11 monogenic obesity genes identified to date and their role in energy maintenance as part of the leptin-melanocortin pathway. With the emergence of genome-wide association studies over the last decade, 227 genetic variants involved in different biological pathways (central nervous system, food sensing and digestion, adipocyte differentiation, insulin signalling, lipid metabolism, muscle and liver biology, gut microbiota) have been associated with polygenic obesity. Advances in obligatory and facilitated epigenetic variation, and gene-environment interaction studies have partly accounted for the missing heritability of obesity and provided additional insight into its aetiology. The role of gut microbiota in obesity pathophysiology, as well as the 12 genes associated with lipodystrophies is discussed. Furthermore, in an attempt to improve future studies and merge the gap between research and clinical practice, we provide suggestions on how high-throughput '-omic' data can be integrated in order to get closer to the new age of personalized medicine. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Bovine spastic paresis: A review of the genetic background and perspectives for the future.

PubMed

Goeckmann, Victoria; Rothammer, Sophie; Medugorac, Ivica

2016-10-01

Bovine spastic paresis (BSP) is a sporadic, progressive neuromuscular disease that is thought to affect all breeds of cattle. The disease manifests as a unilateral or bilateral hyperextension of the hind limb due to increased muscle tone or permanent spasm of mainly the gastrocnemius and/or the quadriceps muscle. Clinical signs only appear in rising, standing and moving animals, which is an important diagnostic feature. Although several medical treatments have been described, surgical procedures such as neurectomy or tenectomy are generally indicated. Even though complete recovery can be achieved, BSP-affected animals should not be used for breeding, since BSP is commonly considered a hereditary disease. The condition therefore negatively affects animal welfare, economics and breeding. When first described in 1922, BSP was already assumed to be heritable, and this assumption has been perpetuated by subsequent authors who have only discussed its possible modes of inheritance, which included monogenetic and polygenetic modes and gene-environment interactions. Besides some clinical aspects and the consideration of the tarsal joint angle as a BSP-correlated trait, this review mainly focuses on the assumed genetic aspects of BSP. Evaluation of the published literature demonstrates that to date, irrevocable proof for the assumed heritability of BSP is still missing. The assumption of heredity is further contradicted by known allele frequencies and incidences of proven hereditary diseases in cattle, such as arachnomelia or bovine spinal muscular atrophy. Consequently, future research is needed to determine the cause of spastic paresis. Procedures that will help test the null-hypothesis ('BSP is not hereditary') and possible modes of inheritance are discussed in this review. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mining the LIPG Allelic Spectrum Reveals the Contribution of Rare and Common Regulatory Variants to HDL Cholesterol

PubMed Central

Raghavan, Avanthi; Neeli, Hemanth; Jin, Weijun; Badellino, Karen O.; Demissie, Serkalem; Manning, Alisa K.; DerOhannessian, Stephanie L.; Wolfe, Megan L.; Cupples, L. Adrienne; Li, Mingyao; Kathiresan, Sekar; Rader, Daniel J.

2011-01-01

Genome-wide association studies (GWAS) have successfully identified loci associated with quantitative traits, such as blood lipids. Deep resequencing studies are being utilized to catalogue the allelic spectrum at GWAS loci. The goal of these studies is to identify causative variants and missing heritability, including heritability due to low frequency and rare alleles with large phenotypic impact. Whereas rare variant efforts have primarily focused on nonsynonymous coding variants, we hypothesized that noncoding variants in these loci are also functionally important. Using the HDL-C gene LIPG as an example, we explored the effect of regulatory variants identified through resequencing of subjects at HDL-C extremes on gene expression, protein levels, and phenotype. Resequencing a portion of the LIPG promoter and 5′ UTR in human subjects with extreme HDL-C, we identified several rare variants in individuals from both extremes. Luciferase reporter assays were used to measure the effect of these rare variants on LIPG expression. Variants conferring opposing effects on gene expression were enriched in opposite extremes of the phenotypic distribution. Minor alleles of a common regulatory haplotype and noncoding GWAS SNPs were associated with reduced plasma levels of the LIPG gene product endothelial lipase (EL), consistent with its role in HDL-C catabolism. Additionally, we found that a common nonfunctional coding variant associated with HDL-C (rs2000813) is in linkage disequilibrium with a 5′ UTR variant (rs34474737) that decreases LIPG promoter activity. We attribute the gene regulatory role of rs34474737 to the observed association of the coding variant with plasma EL levels and HDL-C. Taken together, the findings show that both rare and common noncoding regulatory variants are important contributors to the allelic spectrum in complex trait loci. PMID:22174694

Performance of polygenic scores for predicting phobic anxiety.

PubMed

Walter, Stefan; Glymour, M Maria; Koenen, Karestan; Liang, Liming; Tchetgen Tchetgen, Eric J; Cornelis, Marilyn; Chang, Shun-Chiao; Rimm, Eric; Kawachi, Ichiro; Kubzansky, Laura D

2013-01-01

Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits. To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes. Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort. Study participants (n = 11,127) were individuals from the Nurses' Health Study and Health Professionals Follow-up Study. Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived. We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety. There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20-40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety.

Constructing a Coherent Problem Model to Facilitate Algebra Problem Solving in a Chemistry Context

ERIC Educational Resources Information Center

Ngu, Bing Hiong; Yeung, Alexander Seeshing; Phan, Huy P.

2015-01-01

An experiment using a sample of 11th graders compared text editing and worked examples approaches in learning to solve dilution and molarity algebra word problems in a chemistry context. Text editing requires students to assess the structure of a word problem by specifying whether the problem text contains sufficient, missing, or irrelevant…

Heritable and Nonheritable Pathways to Early Callous-Unemotional Behaviors.

PubMed

Hyde, Luke W; Waller, Rebecca; Trentacosta, Christopher J; Shaw, Daniel S; Neiderhiser, Jenae M; Ganiban, Jody M; Reiss, David; Leve, Leslie D

2016-09-01

Callous-unemotional behaviors in early childhood signal higher risk for trajectories of antisocial behavior and callous-unemotional traits that culminate in later diagnoses of conduct disorder, antisocial personality disorder, and psychopathy. Studies demonstrate high heritability of callous-unemotional traits, but little research has examined specific heritable pathways to early callous-unemotional behaviors. Studies also indicate that positive parenting protects against the development of callous-unemotional traits, but genetically informed designs have not been used to confirm that these relationships are not the product of gene-environment correlations. In a sample of adopted children and their biological and adoptive mothers, the authors tested novel heritable and nonheritable pathways to preschool callous-unemotional behaviors. In an adoption cohort of 561 families, history of severe antisocial behavior assessed in biological mothers and observations of adoptive mother positive reinforcement at 18 months were examined as predictors of callous-unemotional behaviors at 27 months. Despite limited or no contact with offspring, biological mother antisocial behavior predicted early callous-unemotional behaviors. Adoptive mother positive reinforcement protected against early callous-unemotional behaviors. High levels of adoptive mother positive reinforcement buffered the effects of heritable risk for callous-unemotional behaviors posed by biological mother antisocial behavior. The findings elucidate heritable and nonheritable pathways to early callous-unemotional behaviors. The results provide a specific heritable pathway to callous-unemotional behaviors and compelling evidence that parenting is an important nonheritable factor in the development of callous-unemotional behaviors. The finding that positive reinforcement buffered heritable risk for callous-unemotional behaviors has important translational implications for the prevention of trajectories to serious antisocial behavior.

Heritable victimization and the benefits of agonistic relationships

PubMed Central

Lea, Amanda J.; Blumstein, Daniel T.; Wey, Tina W.; Martin, Julien G. A.

2010-01-01

Here, we present estimates of heritability and selection on network traits in a single population, allowing us to address the evolutionary potential of social behavior and the poorly understood link between sociality and fitness. To evolve, sociality must have some heritable basis, yet the heritability of social relationships is largely unknown. Recent advances in both social network analyses and quantitative genetics allow us to quantify attributes of social relationships and estimate their heritability in free-living populations. Our analyses addressed a variety of measures (in-degree, out-degree, attractiveness, expansiveness, embeddedness, and betweenness), and we hypothesized that traits reflecting relationships controlled by an individual (i.e., those that the individual initiated or were directly involved in) would be more heritable than those based largely on the behavior of conspecifics. Identifying patterns of heritability and selection among related traits may provide insight into which types of relationships are important in animal societies. As expected, we found that variation in indirect measures was largely explained by nongenetic variation. Yet, surprisingly, traits capturing initiated interactions do not possess significant additive genetic variation, whereas measures of received interactions are heritable. Measures describing initiated aggression and position in an agonistic network are under selection (0.3 < |S| < 0.4), although advantageous trait values are not inherited by offspring. It appears that agonistic relationships positively influence fitness and seemingly costly or harmful ties may, in fact, be beneficial. Our study highlights the importance of studying agonistic as well as affiliative relationships to understand fully the connections between sociality and fitness. PMID:21115836

Whole genome prediction and heritability of childhood asthma phenotypes.

PubMed

McGeachie, Michael J; Clemmer, George L; Croteau-Chonka, Damien C; Castaldi, Peter J; Cho, Michael H; Sordillo, Joanne E; Lasky-Su, Jessica A; Raby, Benjamin A; Tantisira, Kelan G; Weiss, Scott T

2016-12-01

While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma-related phenotypes. We applied several WGP methods to a well-phenotyped cohort of 832 children with mild-to-moderate asthma from CAMP. We assessed narrow-sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre- and post-bronchodilator forced expiratory volume in 1 sec (FEV 1 ), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort. We found that longitudinal lung function phenotypes demonstrated significant narrow-sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4-8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts. Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP-prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma-related heritable traits.

"Asia's missing women" as a problem in applied evolutionary psychology?

PubMed

Brooks, Robert

2012-12-20

In many parts of Asia, the Middle East and North Africa, women and children are so undervalued, neglected, abused, and so often killed, that sex ratios are now strongly male biased. In recent decades, sex-biased abortion has exacerbated the problem. In this article I highlight several important insights from evolutionary biology into both the origin and the severe societal consequences of "Asia's missing women", paying particular attention to interactions between evolution, economics and culture. Son preferences and associated cultural practices like patrilineal inheritance, patrilocality and the Indian Hindu dowry system arise among the wealthy and powerful elites for reasons consistent with models of sex-biased parental investment. Those practices then spread via imitation as technology gets cheaper and economic development allows the middle class to grow rapidly. I will consider evidence from India, China and elsewhere that grossly male-biased sex ratios lead to increased crime, violence, local warfare, political instability, drug abuse, prostitution and trafficking of women. The problem of Asia's missing women presents a challenge for applied evolutionary psychology to help us understand and ameliorate sex ratio biases and their most severe consequences.

Sampled-data H∞ filtering for Markovian jump singularly perturbed systems with time-varying delay and missing measurements

NASA Astrophysics Data System (ADS)

Yan, Yifang; Yang, Chunyu; Ma, Xiaoping; Zhou, Linna

2018-02-01

In this paper, sampled-data H∞ filtering problem is considered for Markovian jump singularly perturbed systems with time-varying delay and missing measurements. The sampled-data system is represented by a time-delay system, and the missing measurement phenomenon is described by an independent Bernoulli random process. By constructing an ɛ-dependent stochastic Lyapunov-Krasovskii functional, delay-dependent sufficient conditions are derived such that the filter error system satisfies the prescribed H∞ performance for all possible missing measurements. Then, an H∞ filter design method is proposed in terms of linear matrix inequalities. Finally, numerical examples are given to illustrate the feasibility and advantages of the obtained results.

Limb Loss

MedlinePlus

... in amputation. Injuries, including from traffic accidents and military combat Cancer Birth defects Some amputees have phantom pain, which is the feeling of pain in the missing limb. Other physical problems include surgical complications and skin problems, if you ...

Heritability of specific language impairment depends on diagnostic criteria.

PubMed

Bishop, D V M; Hayiou-Thomas, M E

2008-04-01

Heritability estimates for specific language impairment (SLI) have been inconsistent. Four twin studies reported heritability of 0.5 or more, but a recent report from the Twins Early Development Study found negligible genetic influence in 4-year-olds. We considered whether the method of ascertainment influenced results and found substantially higher heritability if SLI was defined in terms of referral to speech and language pathology services than if defined by language test scores. Further analysis showed that presence of speech difficulties played a major role in determining whether a child had contact with services. Childhood language disorders that are identified by population screening are likely to have a different phenotype and different etiology from clinically referred cases. Genetic studies are more likely to find high heritability if they focus on cases who have speech difficulties and who have been referred for intervention.

The Architecture of Parent-of-Origin Effects in Mice

PubMed Central

Mott, Richard; Yuan, Wei; Kaisaki, Pamela; Gan, Xiangchao; Cleak, James; Edwards, Andrew; Baud, Amelie; Flint, Jonathan

2014-01-01

Summary The number of imprinted genes in the mammalian genome is predicted to be small, yet we show here, in a survey of 97 traits measured in outbred mice, that most phenotypes display parent-of-origin effects that are partially confounded with family structure. To address this contradiction, using reciprocal F1 crosses, we investigated the effects of knocking out two nonimprinted candidate genes, Man1a2 and H2-ab1, that reside at nonimprinted loci but that show parent-of-origin effects. We show that expression of multiple genes becomes dysregulated in a sex-, tissue-, and parent-of-origin-dependent manner. We provide evidence that nonimprinted genes can generate parent-of-origin effects by interaction with imprinted loci and deduce that the importance of the number of imprinted genes is secondary to their interactions. We propose that this gene network effect may account for some of the missing heritability seen when comparing sibling-based to population-based studies of the phenotypic effects of genetic variants. PMID:24439386

Simple F Test Reveals Gene-Gene Interactions in Case-Control Studies

PubMed Central

Chen, Guanjie; Yuan, Ao; Zhou, Jie; Bentley, Amy R.; Adeyemo, Adebowale; Rotimi, Charles N.

2012-01-01

Missing heritability is still a challenge for Genome Wide Association Studies (GWAS). Gene-gene interactions may partially explain this residual genetic influence and contribute broadly to complex disease. To analyze the gene-gene interactions in case-control studies of complex disease, we propose a simple, non-parametric method that utilizes the F-statistic. This approach consists of three steps. First, we examine the joint distribution of a pair of SNPs in cases and controls separately. Second, an F-test is used to evaluate the ratio of dependence in cases to that of controls. Finally, results are adjusted for multiple tests. This method was used to evaluate gene-gene interactions that are associated with risk of Type 2 Diabetes among African Americans in the Howard University Family Study. We identified 18 gene-gene interactions (P < 0.0001). Compared with the commonly-used logistical regression method, we demonstrate that the F-ratio test is an efficient approach to measuring gene-gene interactions, especially for studies with limited sample size. PMID:22837643

Discovery and validation of sub-threshold genome-wide association study loci using epigenomic signatures

PubMed Central

Wang, Xinchen; Tucker, Nathan R; Rizki, Gizem; Mills, Robert; Krijger, Peter HL; de Wit, Elzo; Subramanian, Vidya; Bartell, Eric; Nguyen, Xinh-Xinh; Ye, Jiangchuan; Leyton-Mange, Jordan; Dolmatova, Elena V; van der Harst, Pim; de Laat, Wouter; Ellinor, Patrick T; Newton-Cheh, Christopher; Milan, David J; Kellis, Manolis; Boyer, Laurie A

2016-01-01

Genetic variants identified by genome-wide association studies explain only a modest proportion of heritability, suggesting that meaningful associations lie 'hidden' below current thresholds. Here, we integrate information from association studies with epigenomic maps to demonstrate that enhancers significantly overlap known loci associated with the cardiac QT interval and QRS duration. We apply functional criteria to identify loci associated with QT interval that do not meet genome-wide significance and are missed by existing studies. We demonstrate that these 'sub-threshold' signals represent novel loci, and that epigenomic maps are effective at discriminating true biological signals from noise. We experimentally validate the molecular, gene-regulatory, cellular and organismal phenotypes of these sub-threshold loci, demonstrating that most sub-threshold loci have regulatory consequences and that genetic perturbation of nearby genes causes cardiac phenotypes in mouse. Our work provides a general approach for improving the detection of novel loci associated with complex human traits. DOI: http://dx.doi.org/10.7554/eLife.10557.001 PMID:27162171

Prediction accuracies for growth and wood attributes of interior spruce in space using genotyping-by-sequencing.

PubMed

Gamal El-Dien, Omnia; Ratcliffe, Blaise; Klápště, Jaroslav; Chen, Charles; Porth, Ilga; El-Kassaby, Yousry A

2015-05-09

Genomic selection (GS) in forestry can substantially reduce the length of breeding cycle and increase gain per unit time through early selection and greater selection intensity, particularly for traits of low heritability and late expression. Affordable next-generation sequencing technologies made it possible to genotype large numbers of trees at a reasonable cost. Genotyping-by-sequencing was used to genotype 1,126 Interior spruce trees representing 25 open-pollinated families planted over three sites in British Columbia, Canada. Four imputation algorithms were compared (mean value (MI), singular value decomposition (SVD), expectation maximization (EM), and a newly derived, family-based k-nearest neighbor (kNN-Fam)). Trees were phenotyped for several yield and wood attributes. Single- and multi-site GS prediction models were developed using the Ridge Regression Best Linear Unbiased Predictor (RR-BLUP) and the Generalized Ridge Regression (GRR) to test different assumption about trait architecture. Finally, using PCA, multi-trait GS prediction models were developed. The EM and kNN-Fam imputation methods were superior for 30 and 60% missing data, respectively. The RR-BLUP GS prediction model produced better accuracies than the GRR indicating that the genetic architecture for these traits is complex. GS prediction accuracies for multi-site were high and better than those of single-sites while multi-site predictability produced the lowest accuracies reflecting type-b genetic correlations and deemed unreliable. The incorporation of genomic information in quantitative genetics analyses produced more realistic heritability estimates as half-sib pedigree tended to inflate the additive genetic variance and subsequently both heritability and gain estimates. Principle component scores as representatives of multi-trait GS prediction models produced surprising results where negatively correlated traits could be concurrently selected for using PCA2 and PCA3. The application of GS to open-pollinated family testing, the simplest form of tree improvement evaluation methods, was proven to be effective. Prediction accuracies obtained for all traits greatly support the integration of GS in tree breeding. While the within-site GS prediction accuracies were high, the results clearly indicate that single-site GS models ability to predict other sites are unreliable supporting the utilization of multi-site approach. Principle component scores provided an opportunity for the concurrent selection of traits with different phenotypic optima.

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types

PubMed Central

Wheeler, William A.; Yeager, Meredith; Panagiotou, Orestis; Wang, Zhaoming; Berndt, Sonja I.; Lan, Qing; Abnet, Christian C.; Amundadottir, Laufey T.; Figueroa, Jonine D.; Landi, Maria Teresa; Mirabello, Lisa; Savage, Sharon A.; Taylor, Philip R.; Vivo, Immaculata De; McGlynn, Katherine A.; Purdue, Mark P.; Rajaraman, Preetha; Adami, Hans-Olov; Ahlbom, Anders; Albanes, Demetrius; Amary, Maria Fernanda; An, She-Juan; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L.; Angelucci, Emanuele; Ansell, Stephen M.; Arici, Cecilia; Armstrong, Bruce K.; Arslan, Alan A.; Austin, Melissa A.; Baris, Dalsu; Barkauskas, Donald A.; Bassig, Bryan A.; Becker, Nikolaus; Benavente, Yolanda; Benhamou, Simone; Berg, Christine; Van Den Berg, David; Bernstein, Leslie; Bertrand, Kimberly A.; Birmann, Brenda M.; Black, Amanda; Boeing, Heiner; Boffetta, Paolo; Boutron-Ruault, Marie-Christine; Bracci, Paige M.; Brinton, Louise; Brooks-Wilson, Angela R.; Bueno-de-Mesquita, H. Bas; Burdett, Laurie; Buring, Julie; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chan, John K. C.; Chang, Ellen T.; Chang, Gee-Chen; Chang, I-Shou; Chang, Jiang; Chang-Claude, Jenny; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chu; Chen, Chung-Hsing; Chen, Constance; Chen, Hongyan; Chen, Kexin; Chen, Kuan-Yu; Chen, Kun-Chieh; Chen, Ying; Chen, Ying-Hsiang; Chen, Yi-Song; Chen, Yuh-Min; Chien, Li-Hsin; Chirlaque, María-Dolores; Choi, Jin Eun; Choi, Yi Young; Chow, Wong-Ho; Chung, Charles C.; Clavel, Jacqueline; Clavel-Chapelon, Françoise; Cocco, Pierluigi; Colt, Joanne S.; Comperat, Eva; Conde, Lucia; Connors, Joseph M.; Conti, David; Cortessis, Victoria K.; Cotterchio, Michelle; Cozen, Wendy; Crouch, Simon; Crous-Bou, Marta; Cussenot, Olivier; Davis, Faith G.; Ding, Ti; Diver, W. Ryan; Dorronsoro, Miren; Dossus, Laure; Duell, Eric J.; Ennas, Maria Grazia; Erickson, Ralph L.; Feychting, Maria; Flanagan, Adrienne M.; Foretova, Lenka; Fraumeni, Joseph F.; Freedman, Neal D.; Beane Freeman, Laura E.; Fuchs, Charles; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M.; Garcia-Closas, Montserrat; García-Closas, Reina; Gascoyne, Randy D.; Gastier-Foster, Julie; Gaudet, Mia M.; Gaziano, J. Michael; Giffen, Carol; Giles, Graham G.; Giovannucci, Edward; Glimelius, Bengt; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M.; Gorlick, Richard; Gross, Myron; Grubb, Robert; Gu, Jian; Guan, Peng; Gunter, Marc; Guo, Huan; Habermann, Thomas M.; Haiman, Christopher A.; Halai, Dina; Hallmans, Goran; Hassan, Manal; Hattinger, Claudia; He, Qincheng; He, Xingzhou; Helzlsouer, Kathy; Henderson, Brian; Henriksson, Roger; Hjalgrim, Henrik; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holford, Theodore R.; Holly, Elizabeth A.; Hong, Yun-Chul; Hoover, Robert N.; Horn-Ross, Pamela L.; Hosain, G. M. Monawar; Hosgood, H. Dean; Hsiao, Chin-Fu; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Huerta, Jose-Maria; Hung, Jen-Yu; Hutchinson, Amy; Inskip, Peter D.; Jackson, Rebecca D.; Jacobs, Eric J.; Jenab, Mazda; Jeon, Hyo-Sung; Ji, Bu-Tian; Jin, Guangfu; Jin, Li; Johansen, Christoffer; Johnson, Alison; Jung, Yoo Jin; Kaaks, Rudolph; Kamineni, Aruna; Kane, Eleanor; Kang, Chang Hyun; Karagas, Margaret R.; Kelly, Rachel S.; Khaw, Kay-Tee; Kim, Christopher; Kim, Hee Nam; Kim, Jin Hee; Kim, Jun Suk; Kim, Yeul Hong; Kim, Young Tae; Kim, Young-Chul; Kitahara, Cari M.; Klein, Alison P.; Klein, Robert J.; Kogevinas, Manolis; Kohno, Takashi; Kolonel, Laurence N.; Kooperberg, Charles; Kricker, Anne; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C.; Kweon, Sun-Seog; LaCroix, Andrea; Lawrence, Charles; Lecanda, Fernando; Lee, Victor Ho Fun; Li, Donghui; Li, Haixin; Li, Jihua; Li, Yao-Jen; Li, Yuqing; Liao, Linda M.; Liebow, Mark; Lightfoot, Tracy; Lim, Wei-Yen; Lin, Chien-Chung; Lin, Dongxin; Lindstrom, Sara; Linet, Martha S.; Link, Brian K.; Liu, Chenwei; Liu, Jianjun; Liu, Li; Ljungberg, Börje; Lloreta, Josep; Lollo, Simonetta Di; Lu, Daru; Lund, Eiluv; Malats, Nuria; Mannisto, Satu; Marchand, Loic Le; Marina, Neyssa; Masala, Giovanna; Mastrangelo, Giuseppe; Matsuo, Keitaro; Maynadie, Marc; McKay, James; McKean-Cowdin, Roberta; Melbye, Mads; Melin, Beatrice S.; Michaud, Dominique S.; Mitsudomi, Tetsuya; Monnereau, Alain; Montalvan, Rebecca; Moore, Lee E.; Mortensen, Lotte Maxild; Nieters, Alexandra; North, Kari E.; Novak, Anne J.; Oberg, Ann L.; Offit, Kenneth; Oh, In-Jae; Olson, Sara H.; Palli, Domenico; Pao, William; Park, In Kyu; Park, Jae Yong; Park, Kyong Hwa; Patiño-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H. M.; Perng, Reury-Perng; Peters, Ulrike; Petersen, Gloria M.; Picci, Piero; Pike, Malcolm C.; Porru, Stefano; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Qian, Biyun; Qiao, You-Lin; Rais, Marco; Riboli, Elio; Riby, Jacques; Risch, Harvey A.; Rizzato, Cosmeri; Rodabough, Rebecca; Roman, Eve; Roupret, Morgan; Ruder, Avima M.; de Sanjose, Silvia; Scelo, Ghislaine; Schned, Alan; Schumacher, Fredrick; Schwartz, Kendra; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D.; Setiawan, Veronica Wendy; Severi, Gianluca; Severson, Richard K.; Shanafelt, Tait D.; Shen, Hongbing; Shen, Wei; Shin, Min-Ho; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesúmaga, Luis; Sihoe, Alan Dart Loon; Skibola, Christine F.; Smith, Alex; Smith, Martyn T.; Southey, Melissa C.; Spinelli, John J.; Staines, Anthony; Stampfer, Meir; Stern, Marianna C.; Stevens, Victoria L.; Stolzenberg-Solomon, Rachael S.; Su, Jian; Su, Wu-Chou; Sund, Malin; Sung, Jae Sook; Sung, Sook Whan; Tan, Wen; Tang, Wei; Tardón, Adonina; Thomas, David; Thompson, Carrie A.; Tinker, Lesley F.; Tirabosco, Roberto; Tjønneland, Anne; Travis, Ruth C.; Trichopoulos, Dimitrios; Tsai, Fang-Yu; Tsai, Ying-Huang; Tucker, Margaret; Turner, Jenny; Vajdic, Claire M.; Vermeulen, Roel C. H.; Villano, Danylo J.; Vineis, Paolo; Virtamo, Jarmo; Visvanathan, Kala; Wactawski-Wende, Jean; Wang, Chaoyu; Wang, Chih-Liang; Wang, Jiu-Cun; Wang, Junwen; Wei, Fusheng; Weiderpass, Elisabete; Weiner, George J.; Weinstein, Stephanie; Wentzensen, Nicolas; White, Emily; Witzig, Thomas E.; Wolpin, Brian M.; Wong, Maria Pik; Wu, Chen; Wu, Guoping; Wu, Junjie; Wu, Tangchun; Wu, Wei; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S.; Xiang, Yong-Bing; Xu, Jun; Xu, Ping; Yang, Pan-Chyr; Yang, Tsung-Ying; Ye, Yuanqing; Yin, Zhihua; Yokota, Jun; Yoon, Ho-Il; Yu, Chong-Jen; Yu, Herbert; Yu, Kai; Yuan, Jian-Min; Zelenetz, Andrew; Zeleniuch-Jacquotte, Anne; Zhang, Xu-Chao; Zhang, Yawei; Zhao, Xueying; Zhao, Zhenhong; Zheng, Hong; Zheng, Tongzhang; Zheng, Wei; Zhou, Baosen; Zhu, Meng; Zucca, Mariagrazia; Boca, Simina M.; Cerhan, James R.; Ferri, Giovanni M.; Hartge, Patricia; Hsiung, Chao Agnes; Magnani, Corrado; Miligi, Lucia; Morton, Lindsay M.; Smedby, Karin E.; Teras, Lauren R.; Vijai, Joseph; Wang, Sophia S.; Brennan, Paul; Caporaso, Neil E.; Hunter, David J.; Kraft, Peter; Rothman, Nathaniel; Silverman, Debra T.; Slager, Susan L.; Chanock, Stephen J.; Chatterjee, Nilanjan

2015-01-01

Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl 2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation. PMID:26464424

Intrafamilial aggregation and heritability of office-day blood pressure difference in a community of African ancestry: implications for genetic association studies.

PubMed

Djami-Tchatchou, Arnaud T; Norton, Gavin R; Redelinghuys, Michelle; Maseko, Muzi J; Majane, Olebogeng H I; Woodiwiss, Angela J

2014-12-01

An inability to show consistent relationships between gene variants and blood pressure (BP) may be confounded by the use of office BP measurement. Whether the difference between office BP and day BP (office-day) is genetically predetermined is unknown. We therefore aimed to determine the intrafamilial aggregation and heritability of office-day BP. Nurse-derived office BP (mean of 5 measurements according to guidelines) and 24-h ambulatory BP were determined for 592 participants from 198 families (67 spouse pairs, 361 parent-child pairs, and 169 sibling-sibling pairs), with 12 families having three generations, from an urban developing community of black Africans. Heritability estimates were determined using SAGE software. With adjustments for confounders, office systolic BP (SBP) (h=0.35±0.09, P<0.0001) showed comparable heritability estimates to 24-h SBP (h=0.33±0.09, P<0.0001). Similarly, with adjustments for confounders, office diastolic BP (DBP) (h=0.37±0.09, P<0.0001) showed comparable heritability estimates as 24-h DBP (h=0.35±0.09, P<0.0001). However, multivariate adjusted heritability estimates of day SBP (h=0.29±0.09, P<0.0001) and DBP (h=0.33±0.09, P<0.0001) were not diminished by further adjustments for office SBP (h=0.42±0.09, P<0.0001) or DBP (h=0.34±0.09, P<0.0001). Further, independent of confounders, office-day BP showed significant intrafamilial aggregation and heritability (SBP: h=0.51±0.10, P<0.0001; DBP: h=0.37±0.09, P<0.0001), effects that persisted with further adjustments for office, day, or day-night BP (P<0.0005 for SBP and DBP). Although office and ambulatory BP may show similar heritability estimates, genetic associations with carefully determined office BP measurements may be confounded by the heritability of office-day BP differences.

H∞ filtering for discrete-time systems subject to stochastic missing measurements: a decomposition approach

NASA Astrophysics Data System (ADS)

Gu, Zhou; Fei, Shumin; Yue, Dong; Tian, Engang

2014-07-01

This paper deals with the problem of H∞ filtering for discrete-time systems with stochastic missing measurements. A new missing measurement model is developed by decomposing the interval of the missing rate into several segments. The probability of the missing rate in each subsegment is governed by its corresponding random variables. We aim to design a linear full-order filter such that the estimation error converges to zero exponentially in the mean square with a less conservatism while the disturbance rejection attenuation is constrained to a given level by means of an H∞ performance index. Based on Lyapunov theory, the reliable filter parameters are characterised in terms of the feasibility of a set of linear matrix inequalities. Finally, a numerical example is provided to demonstrate the effectiveness and applicability of the proposed design approach.

The effectiveness of supermarket posters in helping to find missing children.

PubMed

Lampinen, James Michael; Arnal, Jack; Hicks, Jason L

2009-03-01

One approach used to help find missing children is to place posters of them at the exits of supermarkets. The present research addresses the question of how effective that approach is likely to be. Posters of 8 missing children were displayed on a bulletin board at a cooperating grocery store. Customers leaving the store completed a survey and took a recognition memory test for the children. Most customers thought the problem of missing children was an important issue. However, the majority of customers also reported either not looking at the posters or only briefly looking at the posters. Recognition memory for children depicted in the posters did not reliably differ from chance. It appears that there is much room for improvement when it comes to increasing the attention paid to posters meant to help find missing children.

Covariance Structure Model Fit Testing under Missing Data: An Application of the Supplemented EM Algorithm

ERIC Educational Resources Information Center

Cai, Li; Lee, Taehun

2009-01-01

We apply the Supplemented EM algorithm (Meng & Rubin, 1991) to address a chronic problem with the "two-stage" fitting of covariance structure models in the presence of ignorable missing data: the lack of an asymptotically chi-square distributed goodness-of-fit statistic. We show that the Supplemented EM algorithm provides a…

The case of the missing third.

PubMed

Robertson, Robin

2005-01-01

How is it that form arises out of chaos? In attempting to deal with this primary question, time and again a "Missing Third" is posited that lies between extremes. The problem of the "Missing Third" can be traced through nearly the entire history of thought. The form it takes, the problems that arise from it, the solutions suggested for resolving it, are each representative of an age. This paper traces the issue from Plato and Parmenides in the 4th--5th centuries, B.C.; to Neoplatonism in the 3rd--5th centuries; to Locke and Descartes in the 17th century; on to Berkeley and Kant in the 18th century; Fechner and Wundt in the 19th century; to behaviorism and Gestalt psychology, Jung, early in the 20th century, ethology and cybernetics later in the 20th century, then culminates late in the 20th century, with chaos theory.

Sensitivity to imputation models and assumptions in receiver operating characteristic analysis with incomplete data

PubMed Central

Karakaya, Jale; Karabulut, Erdem; Yucel, Recai M.

2015-01-01

Modern statistical methods using incomplete data have been increasingly applied in a wide variety of substantive problems. Similarly, receiver operating characteristic (ROC) analysis, a method used in evaluating diagnostic tests or biomarkers in medical research, has also been increasingly popular problem in both its development and application. While missing-data methods have been applied in ROC analysis, the impact of model mis-specification and/or assumptions (e.g. missing at random) underlying the missing data has not been thoroughly studied. In this work, we study the performance of multiple imputation (MI) inference in ROC analysis. Particularly, we investigate parametric and non-parametric techniques for MI inference under common missingness mechanisms. Depending on the coherency of the imputation model with the underlying data generation mechanism, our results show that MI generally leads to well-calibrated inferences under ignorable missingness mechanisms. PMID:26379316

Diagnostic tolerance for missing sensor data

NASA Technical Reports Server (NTRS)

Scarl, Ethan A.

1989-01-01

For practical automated diagnostic systems to continue functioning after failure, they must not only be able to diagnose sensor failures but also be able to tolerate the absence of data from the faulty sensors. It is shown that conventional (associational) diagnostic methods will have combinatoric problems when trying to isolate faulty sensors, even if they adequately diagnose other components. Moreover, attempts to extend the operation of diagnostic capability past sensor failure will necessarily compound those difficulties. Model-based reasoning offers a structured alternative that has no special problems diagnosing faulty sensors and can operate gracefully when sensor data is missing.

The contribution of additive genetic variation to personality variation: heritability of personality.

PubMed

Dochtermann, Ned A; Schwab, Tori; Sih, Andrew

2015-01-07

Individual animals frequently exhibit repeatable differences from other members of their population, differences now commonly referred to as 'animal personality'. Personality differences can arise, for example, from differences in permanent environmental effects--including parental and epigenetic contributors--and the effect of additive genetic variation. Although several studies have evaluated the heritability of behaviour, less is known about general patterns of heritability and additive genetic variation in animal personality. As overall variation in behaviour includes both the among-individual differences that reflect different personalities and temporary environmental effects, it is possible for personality to be largely genetically influenced even when heritability of behaviour per se is quite low. The relative contribution of additive genetic variation to personality variation can be estimated whenever both repeatability and heritability are estimated for the same data. Using published estimates to address this issue, we found that approximately 52% of animal personality variation was attributable to additive genetic variation. Thus, while the heritability of behaviour is often moderate or low, the heritability of personality is much higher. Our results therefore (i) demonstrate that genetic differences are likely to be a major contributor to variation in animal personality and (ii) support the phenotypic gambit: that evolutionary inferences drawn from repeatability estimates may often be justified. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Heritability and genetic integration of tooth size in the South Carolina Gullah.

PubMed

Stojanowski, Christopher M; Paul, Kathleen S; Seidel, Andrew C; Duncan, William N; Guatelli-Steinberg, Debbie

2017-11-01

This article provides estimates of narrow-sense heritability and genetic pleiotropy for mesiodistal tooth dimensions for a sample of 20th century African American individuals. Results inform biological distance analysis and offer insights into patterns of integration in the human dentition. Maximum mesiodistal crown dimensions were measured using Hillson-FitzGerald calipers on 469 stone dental casts from the Menegaz-Bock Collection. Narrow-sense heritability estimates and genetic and phenotypic correlations were estimated using SOLAR 8.1.1 with covariate screening for age, sex, age*sex interaction, and birth year. Heritability estimates were moderate (∼0.10 - 0.90; h 2 mean = 0.51) for most measured variables with sex as the only significant covariate. Patterns of genetic correlation indicate strong integration across tooth classes, except molars. Comparison of these results to previously published work suggests lower overall heritability relative to other human populations and much stronger genetic integration across tooth classes than obtained from nonhuman primate genetic pleiotropy estimates. These results suggest that the high heritabilities previously published may reflect overestimates inherent in previous study designs; as such the standard estimate of 0.55 used in biodistance analyses may not be appropriate. For the Gullah, isolation and endogamy coupled with elevated levels of physiological and economic stress may suppress narrow-sense heritability estimates. Pleiotropy analyses suggest a more highly integrated dentition in humans than in other mammals. © 2017 Wiley Periodicals, Inc.

Use of missing data methods in longitudinal studies: the persistence of bad practices in developmental psychology.

PubMed

Jelicić, Helena; Phelps, Erin; Lerner, Richard M

2009-07-01

Developmental science rests on describing, explaining, and optimizing intraindividual changes and, hence, empirically requires longitudinal research. Problems of missing data arise in most longitudinal studies, thus creating challenges for interpreting the substance and structure of intraindividual change. Using a sample of reports of longitudinal studies obtained from three flagship developmental journals-Child Development, Developmental Psychology, and Journal of Research on Adolescence-we examined the number of longitudinal studies reporting missing data and the missing data techniques used. Of the 100 longitudinal studies sampled, 57 either reported having missing data or had discrepancies in sample sizes reported for different analyses. The majority of these studies (82%) used missing data techniques that are statistically problematic (either listwise deletion or pairwise deletion) and not among the methods recommended by statisticians (i.e., the direct maximum likelihood method and the multiple imputation method). Implications of these results for developmental theory and application, and the need for understanding the consequences of using statistically inappropriate missing data techniques with actual longitudinal data sets, are discussed.

Missing Data in Clinical Studies: Issues and Methods

PubMed Central

Ibrahim, Joseph G.; Chu, Haitao; Chen, Ming-Hui

2012-01-01

Missing data are a prevailing problem in any type of data analyses. A participant variable is considered missing if the value of the variable (outcome or covariate) for the participant is not observed. In this article, various issues in analyzing studies with missing data are discussed. Particularly, we focus on missing response and/or covariate data for studies with discrete, continuous, or time-to-event end points in which generalized linear models, models for longitudinal data such as generalized linear mixed effects models, or Cox regression models are used. We discuss various classifications of missing data that may arise in a study and demonstrate in several situations that the commonly used method of throwing out all participants with any missing data may lead to incorrect results and conclusions. The methods described are applied to data from an Eastern Cooperative Oncology Group phase II clinical trial of liver cancer and a phase III clinical trial of advanced non–small-cell lung cancer. Although the main area of application discussed here is cancer, the issues and methods we discuss apply to any type of study. PMID:22649133

VARIABLE SELECTION FOR REGRESSION MODELS WITH MISSING DATA

PubMed Central

Garcia, Ramon I.; Ibrahim, Joseph G.; Zhu, Hongtu

2009-01-01

We consider the variable selection problem for a class of statistical models with missing data, including missing covariate and/or response data. We investigate the smoothly clipped absolute deviation penalty (SCAD) and adaptive LASSO and propose a unified model selection and estimation procedure for use in the presence of missing data. We develop a computationally attractive algorithm for simultaneously optimizing the penalized likelihood function and estimating the penalty parameters. Particularly, we propose to use a model selection criterion, called the ICQ statistic, for selecting the penalty parameters. We show that the variable selection procedure based on ICQ automatically and consistently selects the important covariates and leads to efficient estimates with oracle properties. The methodology is very general and can be applied to numerous situations involving missing data, from covariates missing at random in arbitrary regression models to nonignorably missing longitudinal responses and/or covariates. Simulations are given to demonstrate the methodology and examine the finite sample performance of the variable selection procedures. Melanoma data from a cancer clinical trial is presented to illustrate the proposed methodology. PMID:20336190

Heritability and genetic correlations for volume, foxtails, and other characteristics of Caribbean pine in Puerto Rico

Treesearch

F. Thomas Ledig; J.L. Whitmore

1981-01-01

Caribbean pine is an important exotic being bred throughout the tropics, but published estimates are lacking for heritability of economically important traits and the genetic correlations between them. Based on a Puerto Rican trial of 16 open-pollinated parents of var. hondurensis selected in Belize, heritabilities for a number of characteristics...

77 FR 47857 - Secretary's Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-08-10

... Advisory Committee on Heritable Disorders in Newborns and Children; Notice of Meeting In accordance with... Disorders in Newborns and Children. Dates and Times: September 13, 2012, 8:30 a.m. to 6:00 p.m., September... Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC), as authorized by Public Law...

Heritable DNA methylation in CD4+ cells among complex families displays genetic and non-genetic effects

USDA-ARS?s Scientific Manuscript database

DNA methylation at CpG sites is both heritable and influenced by environment, but the relative contributions of each to DNA methylation levels are unclear. We conducted a heritability analysis of CpG methylation in human CD4+ cells across 975 individuals from 163 families in the Genetics of Lipid-lo...

Outlier Removal in Model-Based Missing Value Imputation for Medical Datasets.

PubMed

Huang, Min-Wei; Lin, Wei-Chao; Tsai, Chih-Fong

2018-01-01

Many real-world medical datasets contain some proportion of missing (attribute) values. In general, missing value imputation can be performed to solve this problem, which is to provide estimations for the missing values by a reasoning process based on the (complete) observed data. However, if the observed data contain some noisy information or outliers, the estimations of the missing values may not be reliable or may even be quite different from the real values. The aim of this paper is to examine whether a combination of instance selection from the observed data and missing value imputation offers better performance than performing missing value imputation alone. In particular, three instance selection algorithms, DROP3, GA, and IB3, and three imputation algorithms, KNNI, MLP, and SVM, are used in order to find out the best combination. The experimental results show that that performing instance selection can have a positive impact on missing value imputation over the numerical data type of medical datasets, and specific combinations of instance selection and imputation methods can improve the imputation results over the mixed data type of medical datasets. However, instance selection does not have a definitely positive impact on the imputation result for categorical medical datasets.

A Bayesian approach to truncated data sets: An application to Malmquist bias in Supernova Cosmology

NASA Astrophysics Data System (ADS)

March, Marisa Cristina

2018-01-01

A problem commonly encountered in statistical analysis of data is that of truncated data sets. A truncated data set is one in which a number of data points are completely missing from a sample, this is in contrast to a censored sample in which partial information is missing from some data points. In astrophysics this problem is commonly seen in a magnitude limited survey such that the survey is incomplete at fainter magnitudes, that is, certain faint objects are simply not observed. The effect of this `missing data' is manifested as Malmquist bias and can result in biases in parameter inference if it is not accounted for. In Frequentist methodologies the Malmquist bias is often corrected for by analysing many simulations and computing the appropriate correction factors. One problem with this methodology is that the corrections are model dependent. In this poster we derive a Bayesian methodology for accounting for truncated data sets in problems of parameter inference and model selection. We first show the methodology for a simple Gaussian linear model and then go on to show the method for accounting for a truncated data set in the case for cosmological parameter inference with a magnitude limited supernova Ia survey.

Drug Abuse

MedlinePlus

... drugs, including opioids Drug abuse also plays a role in many major social problems, such as drugged driving, violence, stress, and child abuse. Drug abuse can lead to homelessness, crime, and missed work or problems with keeping a job. It harms ...

Math Is Not a Problem...When You Know How to Visualize It.

ERIC Educational Resources Information Center

Nelson, Dennis W.

1983-01-01

Visualization is an effective technique for determining exactly what students must do to solve a mathematics problem. Pictures and charts can be used to help children understand which mathematics facts are present and which are missing--an important step toward problem solving. (PP)

Tensor completion for estimating missing values in visual data.

PubMed

Liu, Ji; Musialski, Przemyslaw; Wonka, Peter; Ye, Jieping

2013-01-01

In this paper, we propose an algorithm to estimate missing values in tensors of visual data. The values can be missing due to problems in the acquisition process or because the user manually identified unwanted outliers. Our algorithm works even with a small amount of samples and it can propagate structure to fill larger missing regions. Our methodology is built on recent studies about matrix completion using the matrix trace norm. The contribution of our paper is to extend the matrix case to the tensor case by proposing the first definition of the trace norm for tensors and then by building a working algorithm. First, we propose a definition for the tensor trace norm that generalizes the established definition of the matrix trace norm. Second, similarly to matrix completion, the tensor completion is formulated as a convex optimization problem. Unfortunately, the straightforward problem extension is significantly harder to solve than the matrix case because of the dependency among multiple constraints. To tackle this problem, we developed three algorithms: simple low rank tensor completion (SiLRTC), fast low rank tensor completion (FaLRTC), and high accuracy low rank tensor completion (HaLRTC). The SiLRTC algorithm is simple to implement and employs a relaxation technique to separate the dependent relationships and uses the block coordinate descent (BCD) method to achieve a globally optimal solution; the FaLRTC algorithm utilizes a smoothing scheme to transform the original nonsmooth problem into a smooth one and can be used to solve a general tensor trace norm minimization problem; the HaLRTC algorithm applies the alternating direction method of multipliers (ADMMs) to our problem. Our experiments show potential applications of our algorithms and the quantitative evaluation indicates that our methods are more accurate and robust than heuristic approaches. The efficiency comparison indicates that FaLTRC and HaLRTC are more efficient than SiLRTC and between FaLRTC an- HaLRTC the former is more efficient to obtain a low accuracy solution and the latter is preferred if a high-accuracy solution is desired.

Modeling the Covariance Structure of Complex Datasets Using Cognitive Models: An Application to Individual Differences and the Heritability of Cognitive Ability.

PubMed

Evans, Nathan J; Steyvers, Mark; Brown, Scott D

2018-06-05

Understanding individual differences in cognitive performance is an important part of understanding how variations in underlying cognitive processes can result in variations in task performance. However, the exploration of individual differences in the components of the decision process-such as cognitive processing speed, response caution, and motor execution speed-in previous research has been limited. Here, we assess the heritability of the components of the decision process, with heritability having been a common aspect of individual differences research within other areas of cognition. Importantly, a limitation of previous work on cognitive heritability is the underlying assumption that variability in response times solely reflects variability in the speed of cognitive processing. This assumption has been problematic in other domains, due to the confounding effects of caution and motor execution speed on observed response times. We extend a cognitive model of decision-making to account for relatedness structure in a twin study paradigm. This approach can separately quantify different contributions to the heritability of response time. Using data from the Human Connectome Project, we find strong evidence for the heritability of response caution, and more ambiguous evidence for the heritability of cognitive processing speed and motor execution speed. Our study suggests that the assumption made in previous studies-that the heritability of cognitive ability is based on cognitive processing speed-may be incorrect. More generally, our methodology provides a useful avenue for future research in complex data that aims to analyze cognitive traits across different sources of related data, whether the relation is between people, tasks, experimental phases, or methods of measurement. © 2018 Cognitive Science Society, Inc.

Determinants and Heritability of Intraocular Pressure and Cup-to-Disc Ratio in a Defined Older Population

PubMed Central

Chang, Ta C.; Congdon, Nathan G.; Wojciechowski, Robert; Muñoz, Beatriz; Gilbert, Donna; Chen, Ping; Friedman, David S.; West, Sheila K.

2011-01-01

Purpose To investigate the heritability of intraocular pressure (IOP) and cup-to-disc ratio (CDR) in an older well-defined population. Design Family-based cohort study. Participants Through the population-based Salisbury Eye Evaluation study, we recruited 726 siblings (mean age, 74.7 years) in 284 sibships. Methods Intraocular pressure and CDR were measured bilaterally for all participants. The presence or absence of glaucoma was determined by a glacuoma specialist for all probands on the basis of visual field, optic nerve appearance, and history. The heritability of IOP was calculated as twice the residual between-sibling correlation of IOP using linear regression and generalized estimating equations after adjusting for age, gender, mean arterial pressure, race, self-reported diabetes status, and history of systemic steroid use. The heritability of CDR was calculated using the same model and adjustments as above, while also adjusting for IOP. Main Outcome Measures Heritability and determinants of IOP and CDR, and impact of siblings’ glaucoma status on IOP and CDR. Results We estimated the heritability to be 0.29 (95% confidence interval [CI], 0.12–0.46) for IOP and 0.56 (95% CI, 0.35–0.76) for CDR in this population. Mean IOP in siblings of glaucomatous probands was statistically significantly higher than in siblings of normal probands (mean difference, 1.02 mmHg; P = 0.017). The mean CDR in siblings of glaucomatous probands was 0.07 (or 19%) larger than in siblings of glaucoma suspect referrals (P = 0.045) and siblings of normal probands (P = 0.004). Conclusions In this elderly population, we found CDR to be highly heritable and IOP to be moderately heritable. On average, siblings of glaucoma patients had higher IOPs and larger CDRs than siblings of nonglaucomatous probands. PMID:15939473

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

PubMed

Ferentinos, P; Koukounari, A; Power, R; Rivera, M; Uher, R; Craddock, N; Owen, M J; Korszun, A; Jones, L; Jones, I; Gill, M; Rice, J P; Ising, M; Maier, W; Mors, O; Rietschel, M; Preisig, M; Binder, E B; Aitchison, K J; Mendlewicz, J; Souery, D; Hauser, J; Henigsberg, N; Breen, G; Craig, I W; Farmer, A E; Müller-Myhsok, B; McGuffin, P; Lewis, C M

2015-07-01

Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

A Veritable Menagerie of Heritable Bacteria from Ants, Butterflies, and Beyond: Broad Molecular Surveys and a Systematic Review

PubMed Central

Russell, Jacob A.; Funaro, Colin F.; Giraldo, Ysabel M.; Goldman-Huertas, Benjamin; Suh, David; Kronauer, Daniel J. C.; Moreau, Corrie S.; Pierce, Naomi E.

2012-01-01

Maternally transmitted bacteria have been important players in the evolution of insects and other arthropods, affecting their nutrition, defense, development, and reproduction. Wolbachia are the best studied among these and typically the most prevalent. While several other bacteria have independently evolved a heritable lifestyle, less is known about their host ranges. Moreover, most groups of insects have not had their heritable microflora systematically surveyed across a broad range of their taxonomic diversity. To help remedy these shortcomings we used diagnostic PCR to screen for five groups of heritable symbionts—Arsenophonus spp., Cardinium hertigii, Hamiltonella defensa, Spiroplasma spp., and Wolbachia spp.—across the ants and lepidopterans (focusing, in the latter case, on two butterfly families—the Lycaenidae and Nymphalidae). We did not detect Cardinium or Hamiltonella in any host. Wolbachia were the most widespread, while Spiroplasma (ants and lepidopterans) and Arsenophonus (ants only) were present at low levels. Co-infections with different Wolbachia strains appeared especially common in ants and less so in lepidopterans. While no additional facultative heritable symbionts were found among ants using universal bacterial primers, microbes related to heritable enteric bacteria were detected in several hosts. In summary, our findings show that Wolbachia are the dominant heritable symbionts of ants and at least some lepidopterans. However, a systematic review of symbiont frequencies across host taxa revealed that this is not always the case across other arthropods. Furthermore, comparisons of symbiont frequencies revealed that the prevalence of Wolbachia and other heritable symbionts varies substantially across lower-level arthropod taxa. We discuss the correlates, potential causes, and implications of these patterns, providing hypotheses on host attributes that may shape the distributions of these influential bacteria. PMID:23284655

Inferential Precision in Single-Case Time-Series Data Streams: How Well Does the EM Procedure Perform When Missing Observations Occur in Autocorrelated Data?

PubMed Central

Smith, Justin D.; Borckardt, Jeffrey J.; Nash, Michael R.

2013-01-01

The case-based time-series design is a viable methodology for treatment outcome research. However, the literature has not fully addressed the problem of missing observations with such autocorrelated data streams. Mainly, to what extent do missing observations compromise inference when observations are not independent? Do the available missing data replacement procedures preserve inferential integrity? Does the extent of autocorrelation matter? We use Monte Carlo simulation modeling of a single-subject intervention study to address these questions. We find power sensitivity to be within acceptable limits across four proportions of missing observations (10%, 20%, 30%, and 40%) when missing data are replaced using the Expectation-Maximization Algorithm, more commonly known as the EM Procedure (Dempster, Laird, & Rubin, 1977).This applies to data streams with lag-1 autocorrelation estimates under 0.80. As autocorrelation estimates approach 0.80, the replacement procedure yields an unacceptable power profile. The implications of these findings and directions for future research are discussed. PMID:22697454

On the nature and nurture of intelligence and specific cognitive abilities: the more heritable, the more culture dependent.

PubMed

Kan, Kees-Jan; Wicherts, Jelte M; Dolan, Conor V; van der Maas, Han L J

2013-12-01

To further knowledge concerning the nature and nurture of intelligence, we scrutinized how heritability coefficients vary across specific cognitive abilities both theoretically and empirically. Data from 23 twin studies (combined N = 7,852) showed that (a) in adult samples, culture-loaded subtests tend to demonstrate greater heritability coefficients than do culture-reduced subtests; and (b) in samples of both adults and children, a subtest's proportion of variance shared with general intelligence is a function of its cultural load. These findings require an explanation because they do not follow from mainstream theories of intelligence. The findings are consistent with our hypothesis that heritability coefficients differ across cognitive abilities as a result of differences in the contribution of genotype-environment covariance. The counterintuitive finding that the most heritable abilities are the most culture-dependent abilities sheds a new light on the long-standing nature-nurture debate of intelligence.

Heritable DNA methylation marks associated with susceptibility to breast cancer.

PubMed

Joo, Jihoon E; Dowty, James G; Milne, Roger L; Wong, Ee Ming; Dugué, Pierre-Antoine; English, Dallas; Hopper, John L; Goldgar, David E; Giles, Graham G; Southey, Melissa C

2018-02-28

Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.

Paternal ADHD symptoms and child conduct problems: is father involvement always beneficial?

PubMed

Romirowsky, A M; Chronis-Tuscano, A

2014-09-01

Maternal psychopathology robustly predicts poor developmental and treatment outcomes for children with attention-deficit/hyperactivity disorder (ADHD). Despite the high heritability of ADHD, few studies have examined associations between paternal ADHD symptoms and child adjustment, and none have also considered degree of paternal involvement in childrearing. Identification of modifiable risk factors for child conduct problems is particularly important in this population given the serious adverse outcomes resulting from this comorbidity. This cross-sectional study examined the extent to which paternal involvement in childrearing moderated the association between paternal ADHD symptoms and child conduct problems among 37 children with ADHD and their biological fathers. Neither paternal ADHD symptoms nor involvement was independently associated with child conduct problems. However, the interaction between paternal ADHD symptoms and involvement was significant, such that paternal ADHD symptoms were positively associated with child conduct problems only when fathers were highly involved in childrearing. The presence of adult ADHD symptoms may determine whether father involvement in childrearing has a positive or detrimental influence on comorbid child conduct problems.

Integrative missing value estimation for microarray data.

PubMed

Hu, Jianjun; Li, Haifeng; Waterman, Michael S; Zhou, Xianghong Jasmine

2006-10-12

Missing value estimation is an important preprocessing step in microarray analysis. Although several methods have been developed to solve this problem, their performance is unsatisfactory for datasets with high rates of missing data, high measurement noise, or limited numbers of samples. In fact, more than 80% of the time-series datasets in Stanford Microarray Database contain less than eight samples. We present the integrative Missing Value Estimation method (iMISS) by incorporating information from multiple reference microarray datasets to improve missing value estimation. For each gene with missing data, we derive a consistent neighbor-gene list by taking reference data sets into consideration. To determine whether the given reference data sets are sufficiently informative for integration, we use a submatrix imputation approach. Our experiments showed that iMISS can significantly and consistently improve the accuracy of the state-of-the-art Local Least Square (LLS) imputation algorithm by up to 15% improvement in our benchmark tests. We demonstrated that the order-statistics-based integrative imputation algorithms can achieve significant improvements over the state-of-the-art missing value estimation approaches such as LLS and is especially good for imputing microarray datasets with a limited number of samples, high rates of missing data, or very noisy measurements. With the rapid accumulation of microarray datasets, the performance of our approach can be further improved by incorporating larger and more appropriate reference datasets.

Marginalized zero-inflated Poisson models with missing covariates.

PubMed

Benecha, Habtamu K; Preisser, John S; Divaris, Kimon; Herring, Amy H; Das, Kalyan

2018-05-11

Unlike zero-inflated Poisson regression, marginalized zero-inflated Poisson (MZIP) models for counts with excess zeros provide estimates with direct interpretations for the overall effects of covariates on the marginal mean. In the presence of missing covariates, MZIP and many other count data models are ordinarily fitted using complete case analysis methods due to lack of appropriate statistical methods and software. This article presents an estimation method for MZIP models with missing covariates. The method, which is applicable to other missing data problems, is illustrated and compared with complete case analysis by using simulations and dental data on the caries preventive effects of a school-based fluoride mouthrinse program. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Algebra Word Problem Solving Approaches in a Chemistry Context: Equation Worked Examples versus Text Editing

ERIC Educational Resources Information Center

Ngu, Bing Hiong; Yeung, Alexander Seeshing

2013-01-01

Text editing directs students' attention to the problem structure as they classify whether the texts of word problems contain sufficient, missing or irrelevant information for working out a solution. Equation worked examples emphasize the formation of a coherent problem structure to generate a solution. Its focus is on the construction of three…

Gender Differences in Solution of Algebraic Word Problems Containing Irrelevant Information.

ERIC Educational Resources Information Center

Low, Renae; Over, Ray

1993-01-01

Female tenth graders (n=217) were less likely than male tenth graders (n=219) to identify missing or irrelevant information in algebra problems. Female eleventh graders (n=234) were less likely than male eleventh graders (n=287) to solve problems with irrelevant information. Results indicate sex differences in knowledge of problem structure. (SLD)

Heritability of Two Morphological Characters within and among Natural Populations of Drosophila melanogaster

PubMed Central

Coyne, Jerry A.; Beecham, Edward

1987-01-01

Heritabilities of wing length and abdominal bristle number, as well as genetic correlations between these characters, were determined within and among populations of Drosophila melanogaster in nature. Substantial "natural" heritabilities were found when wild-caught flies from one population were compared to their laboratory-reared offspring. Natural heritabilities of bristle number approximated those derived from laboratory-raised parents and offspring, but wing length heritability was significantly lower in nature than in the laboratory. Among-population heritabilities, estimated by regressing population means of wild-caught flies against those of their laboratory-reared descendants, were close to 0.5. The genetic differentiation of populations was clinal with latitude, and was accompanied by significant geographic differences in the norms of reaction to temperature. These clines are similar to those reported on other continents and in other Drosophila species, and are almost certainly caused by natural selection. Genetic regressions between the characters reveal that the cline in bristle number may be a correlated response to geographic selection on wing length, but not vice versa. Our results indicate that there is a sizable genetic component to phenotypic variation within and among populations of D. melanogaster in nature. PMID:3123311

Guide to Understanding Moebius Syndrome

MedlinePlus

... due to upper body weakness • Strabismus (crossed eyes) • Dry eyes and irritability • Dental problems • High palate • Cleft palate • Hand and feet problems including club foot and missing or fused fingers (syndactyly) • Hearing problems • Poland’s syndrome (chest wall and upper limb anomalies) Although they ...

Teaching Pronunciation in the Learner-Centered Classroom.

ERIC Educational Resources Information Center

Lin, Hsiang-Pao; And Others

Specific tools and techniques to help students of English as a Second Language overcome pronunciation problems are presented. The selection of problems addressed is based on the frequency and seriousness of errors that many native Chinese-speaking learners produce. Ways to resolve various problems (e.g., missing final consonants, misplaced stress…

Prediction of missing common genes for disease pairs using network based module separation on incomplete human interactome.

PubMed

Akram, Pakeeza; Liao, Li

2017-12-06

Identification of common genes associated with comorbid diseases can be critical in understanding their pathobiological mechanism. This work presents a novel method to predict missing common genes associated with a disease pair. Searching for missing common genes is formulated as an optimization problem to minimize network based module separation from two subgraphs produced by mapping genes associated with disease onto the interactome. Using cross validation on more than 600 disease pairs, our method achieves significantly higher average receiver operating characteristic ROC Score of 0.95 compared to a baseline ROC score 0.60 using randomized data. Missing common genes prediction is aimed to complete gene set associated with comorbid disease for better understanding of biological intervention. It will also be useful for gene targeted therapeutics related to comorbid diseases. This method can be further considered for prediction of missing edges to complete the subgraph associated with disease pair.

OPATs: Omnibus P-value association tests.

PubMed

Chen, Chia-Wei; Yang, Hsin-Chou

2017-07-10

Combining statistical significances (P-values) from a set of single-locus association tests in genome-wide association studies is a proof-of-principle method for identifying disease-associated genomic segments, functional genes and biological pathways. We review P-value combinations for genome-wide association studies and introduce an integrated analysis tool, Omnibus P-value Association Tests (OPATs), which provides popular analysis methods of P-value combinations. The software OPATs programmed in R and R graphical user interface features a user-friendly interface. In addition to analysis modules for data quality control and single-locus association tests, OPATs provides three types of set-based association test: window-, gene- and biopathway-based association tests. P-value combinations with or without threshold and rank truncation are provided. The significance of a set-based association test is evaluated by using resampling procedures. Performance of the set-based association tests in OPATs has been evaluated by simulation studies and real data analyses. These set-based association tests help boost the statistical power, alleviate the multiple-testing problem, reduce the impact of genetic heterogeneity, increase the replication efficiency of association tests and facilitate the interpretation of association signals by streamlining the testing procedures and integrating the genetic effects of multiple variants in genomic regions of biological relevance. In summary, P-value combinations facilitate the identification of marker sets associated with disease susceptibility and uncover missing heritability in association studies, thereby establishing a foundation for the genetic dissection of complex diseases and traits. OPATs provides an easy-to-use and statistically powerful analysis tool for P-value combinations. OPATs, examples, and user guide can be downloaded from http://www.stat.sinica.edu.tw/hsinchou/genetics/association/OPATs.htm. © The Author 2017. Published by Oxford University Press.

Insertional translocation leading to a 4q13 duplication including the EPHA5 gene in two siblings with attention-deficit hyperactivity disorder.

PubMed

Matoso, Eunice; Melo, Joana B; Ferreira, Susana I; Jardim, Ana; Castelo, Teresa M; Weise, Anja; Carreira, Isabel M

2013-08-01

An insertional translocation (IT) can result in pure segmental aneusomy for the inserted genomic segment allowing to define a more accurate clinical phenotype. Here, we report on two siblings sharing an unbalanced IT inherited from the mother with a history of learning difficulty. An 8-year-old girl with developmental delay, speech disability, and attention-deficit hyperactivity disorder (ADHD), showed by GTG banding analysis a subtle interstitial alteration in 21q21. Oligonucleotide array comparative genomic hybridization (array-CGH) analysis showed a 4q13.1-q13.3 duplication spanning 8.6 Mb. Fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) clones confirmed the rearrangement, a der(21)ins(21;4)(q21;q13.1q13.3). The duplication described involves 50 RefSeq genes including the EPHA5 gene that encodes for the EphA5 receptor involved in embryonic development of the brain and also in synaptic remodeling and plasticity thought to underlie learning and memory. The same rearrangement was observed in a younger brother with behavioral problems and also exhibiting ADHD. ADHD is among the most heritable of neuropsychiatric disorders. There are few reports of patients with duplications involving the proximal region of 4q and a mild phenotype. To the best of our knowledge this is the first report of a duplication restricted to band 4q13. This abnormality could be easily missed in children who have nonspecific cognitive impairment. The presence of this behavioral disorder in the two siblings reinforces the hypothesis that the region involved could include genes involved in ADHD. Copyright © 2013 Wiley Periodicals, Inc.

The evolution of individuality revisited.

PubMed

Radzvilavicius, Arunas L; Blackstone, Neil W

2018-03-25

Evolutionary theory is formulated in terms of individuals that carry heritable information and are subject to selective pressures. However, individuality itself is a trait that had to evolve - an individual is not an indivisible entity, but a result of evolutionary processes that necessarily begin at the lower level of hierarchical organisation. Traditional approaches to biological individuality focus on cooperation and relatedness within a group, division of labour, policing mechanisms and strong selection at the higher level. Nevertheless, despite considerable theoretical progress in these areas, a full dynamical first-principles account of how new types of individuals arise is missing. To the extent that individuality is an emergent trait, the problem can be approached by recognising the importance of individuating mechanisms that are present from the very beginning of the transition, when only lower-level selection is acting. Here we review some of the most influential theoretical work on the role of individuating mechanisms in these transitions, and demonstrate how a lower-level, bottom-up evolutionary framework can be used to understand biological complexity involved in the origin of cellular life, early eukaryotic evolution, sexual life cycles and multicellular development. Some of these mechanisms inevitably stem from environmental constraints, population structure and ancestral life cycles. Others are unique to specific transitions - features of the natural history and biochemistry that are co-opted into conflict mediation. Identifying mechanisms of individuation that provide a coarse-grained description of the system's evolutionary dynamics is an important step towards understanding how biological complexity and hierarchical organisation evolves. In this way, individuality can be reconceptualised as an approximate model that with varying degrees of precision applies to a wide range of biological systems. © 2018 Cambridge Philosophical Society.

Leveraging multiple gene networks to prioritize GWAS candidate genes via network representation learning.

PubMed

Wu, Mengmeng; Zeng, Wanwen; Liu, Wenqiang; Lv, Hairong; Chen, Ting; Jiang, Rui

2018-06-03

Genome-wide association studies (GWAS) have successfully discovered a number of disease-associated genetic variants in the past decade, providing an unprecedented opportunity for deciphering genetic basis of human inherited diseases. However, it is still a challenging task to extract biological knowledge from the GWAS data, due to such issues as missing heritability and weak interpretability. Indeed, the fact that the majority of discovered loci fall into noncoding regions without clear links to genes has been preventing the characterization of their functions and appealing for a sophisticated approach to bridge genetic and genomic studies. Towards this problem, network-based prioritization of candidate genes, which performs integrated analysis of gene networks with GWAS data, has emerged as a promising direction and attracted much attention. However, most existing methods overlook the sparse and noisy properties of gene networks and thus may lead to suboptimal performance. Motivated by this understanding, we proposed a novel method called REGENT for integrating multiple gene networks with GWAS data to prioritize candidate genes for complex diseases. We leveraged a technique called the network representation learning to embed a gene network into a compact and robust feature space, and then designed a hierarchical statistical model to integrate features of multiple gene networks with GWAS data for the effective inference of genes associated with a disease of interest. We applied our method to six complex diseases and demonstrated the superior performance of REGENT over existing approaches in recovering known disease-associated genes. We further conducted a pathway analysis and showed that the ability of REGENT to discover disease-associated pathways. We expect to see applications of our method to a broad spectrum of diseases for post-GWAS analysis. REGENT is freely available at https://github.com/wmmthu/REGENT. Copyright © 2018 Elsevier Inc. All rights reserved.

Understanding Neurodevelopmental Disorders: The Promise of Regulatory Variation in the 3'UTRome.

PubMed

Wanke, Kai A; Devanna, Paolo; Vernes, Sonja C

2018-04-01

Neurodevelopmental disorders have a strong genetic component, but despite widespread efforts, the specific genetic factors underlying these disorders remain undefined for a large proportion of affected individuals. Given the accessibility of exome sequencing, this problem has thus far been addressed from a protein-centric standpoint; however, protein-coding regions only make up ∼1% to 2% of the human genome. With the advent of whole genome sequencing we are in the midst of a paradigm shift as it is now possible to interrogate the entire sequence of the human genome (coding and noncoding) to fill in the missing heritability of complex disorders. These new technologies bring new challenges, as the number of noncoding variants identified per individual can be overwhelming, making it prudent to focus on noncoding regions of known function, for which the effects of variation can be predicted and directly tested to assess pathogenicity. The 3'UTRome is a region of the noncoding genome that perfectly fulfills these criteria and is of high interest when searching for pathogenic variation related to complex neurodevelopmental disorders. Herein, we review the regulatory roles of the 3'UTRome as binding sites for microRNAs or RNA binding proteins, or during alternative polyadenylation. We detail existing evidence that these regions contribute to neurodevelopmental disorders and outline strategies for identification and validation of novel putatively pathogenic variation in these regions. This evidence suggests that studying the 3'UTRome will lead to the identification of new risk factors, new candidate disease genes, and a better understanding of the molecular mechanisms contributing to neurodevelopmental disorders. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Heritabilities of somatotype components in a population from rural Mozambique.

PubMed

Saranga, Sílvio Pedro José; Prista, António; Nhantumbo, Leonardo; Beunen, Gaston; Rocha, Jorge; Williams-Blangero, Sarah; Maia, José A

2008-01-01

There have been few genetic studies of normal variation in body size and composition conducted in Africa. In particular, the genetic determinants of somatotype remain to be established for an African population. (1) To estimate the heritabilities of aspects of somatotype and (2) to compare the quantitative genetic effects in an African population to those that have been assessed in European and American populations. The sample composed of 329 subjects (173 males and 156 females) aged 7-17 years, belonging to 132 families. The sibships in the sample ranged in size from two to seven individuals. All sampled individuals were residents of the Calanga region, an area located to the north of Maputo in Mozambique. Somatotype was assessed using the Heath-Carter technique. Herit abilities were estimated using SAGE software. Moderate heritabilities were determined for each trait. Between 30 and 40% of the variation in each somatotype measure was attributable to genetic factors. The heritability of ectomorphy was 31%. Mesomorphy was similarly moderately heritable, with approximately 30% of the variationattributable to genetic factors. The heritability of endomorph was higher in the Calanga population (h(2) = 0.40). Quantitative genetic analyses of somatotype variation among siblings indicate that genetic factors significantly influence endomorphy, mesomorhpy, and ectomorphy. However, environmental factors also have significant effects on the variation in physique present in the population of Calanga. Lack of proper nutrition, housing, medical assistance, and primary health care, together with very demanding and sex-specific daily chores may contribute to the environmental effects on these traits.

Chemotherapy induced toxicity is highly heritable in Drosophila melanogaster

PubMed Central

Kislukhin, Galina; Murphy, Maura L.; Jafari, Mahtab; Long, Anthony D.

2012-01-01

Objectives Identifying the genes responsible for chemotherapy toxicity in Drosophila melanogaster may allow for the identification of human orthologs that similarly mediate toxicity in humans. In order to develop Drosophila melanogaster as a model of dissecting chemotoxicity, we first need to develop standardized high throughput toxicity assays and prove that inter-individual variation in toxicity as measured by such assays is highly heritable. Methods We developed a method for the oral delivery of commonly used chemotherapy drugs to Drosophila. Post-treatment female fecundity displayed a dose dependent response to varying levels of the chemotherapy drug delivered. We fixed the dose for each drug at a level that resulted in a 50% reduction in fecundity and used a paternal half-sibling heritability design to calculate the heritability attributable to chemotherapy toxicity assayed via a decrease in female fecundity. Chemotherapy agents tested were carboplatin, floxuridine, gemcitabine hydrochloride, methotrexate, mitomycin C, and topotecan hydrochloride. Results We found that six currently widely prescribed chemotherapeutic agents lowered fecundity in D. melanogaster in both a dose dependent and highly heritable manner. The following heritability estimates were found: carboplatin – 0.72, floxuridine – 0.52, gemcitabine hydrochloride – 0.72, methotrexate – 0.99, mitomycin C – 0.64, and topotecan hydrochloride – 0.63. Conclusions The high heritability estimates observed in this study, irrespective of the particular class of drug examined, suggest that human toxicity may also have a sizable genetic component. PMID:22336958

Missed injuries during the initial assessment in a cohort of 1124 level-1 trauma patients.

PubMed

Giannakopoulos, G F; Saltzherr, T P; Beenen, L F M; Reitsma, J B; Bloemers, F W; Goslings, J C; Bakker, F C

2012-09-01

Despite the presence of diagnostic guidelines for the initial evaluation in trauma, the reported incidence of missed injuries is considerable. The aim of this study was to assess the missed injuries in a large cohort of trauma patients originating from two European Level-1 trauma centres. We analysed the 1124 patients included in the randomised REACT trial. Missed injuries were defined as injuries not diagnosed or suspected during initial clinical and radiological evaluation in the trauma room. We assessed the frequency, type, consequences and the phase in which the missed injuries were diagnosed and used univariate analysis to identify potential contributing factors. Eight hundred and three patients were male, median age was 38 years and 1079 patients sustained blunt trauma. Overall, 122 injuries were missed in 92 patients (8.2%). Most injuries concerned the extremities. Sixteen injuries had an AIS grade of ≥ 3. Patients with missed injuries had significantly higher injury severity scores (ISSs) (median of 15 versus 5, p<0.001). Factors associated with missed injuries were severe traumatic brain injury (GCS ≤ 8) and multitrauma (ISS ≥ 16). Seventy-two missed injuries remained undetected during tertiary survey (59%). In total, 31 operations were required for 26 initially missed injuries. Despite guidelines to avoid missed injuries, this problem is hard to prevent, especially in the severely injured. The present study showed that the rate of missed injuries was comparable with the literature and their consequences not severe. A high index of suspicion remains warranted, especially in multitrauma patients. Copyright © 2011 Elsevier Ltd. All rights reserved.

Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens

PubMed Central

Zeng, Y.; Yin, T.; Brügemann, K.

2018-01-01

Host genetic architecture is a major factor in resistance to pathogens and parasites. The collection and analysis of sufficient data on both disease resistance and host genetics has, however, been a major obstacle to dissection the genetics of resistance to single or multiple pathogens. A severe challenge in the estimation of heritabilities and genetic correlations from pedigree-based studies has been the confounding effects of the common environment shared among relatives which are difficult to model in pedigree analyses, especially for health traits with low incidence rates. To circumvent this problem we used genome-wide single-nucleotide polymorphism data and implemented the Genomic-Restricted Maximum Likelihood (G-REML) method to estimate the heritabilities and genetic correlations for resistance to 23 different infectious pathogens in calves and cows in populations undergoing natural pathogen challenge. Furthermore, we conducted gene-based analysis and generalized gene-set analysis to understand the biological background of resistance to infectious diseases. The results showed relatively higher heritabilities of resistance in calves than in cows and significant pleiotropy (both positive and negative) among some calf and cow resistance traits. We also found significant pleiotropy between resistance and performance in both calves and cows. Finally, we confirmed the role of the B-lymphocyte pathway as one of the most important biological pathways associated with resistance to all pathogens. These results both illustrate the potential power of these approaches to illuminate the genetics of pathogen resistance in cattle and provide foundational information for future genomic selection aimed at improving the overall production fitness of cattle. PMID:29608619

Age trends in genetic control of Juglans nigra L. height growth

Treesearch

George Rink; F. H. Kung

1995-01-01

Age-related trends in narrow-sense and family heritabilities for black walnut height and dbh from a southern Illinois open-pollinated progeny test are evaluated through age 20 years. Narrow-sense heritability for height tends to be relatively stable between ages 10 and 20 at 0.55 - 0.65 with similar patterns and values for family heritabilities for both height and dbh...

Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents.

PubMed

Sieradzka, Dominika; Power, Robert A; Freeman, Daniel; Cardno, Alastair G; Dudbridge, Frank; Ronald, Angelica

2015-09-01

Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended.

Heritability of Craniofacial Structures in Normal Subjects and Patients with Sleep Apnea

PubMed Central

Chi, Luqi; Comyn, Francois-Louis; Keenan, Brendan T.; Cater, Jacqueline; Maislin, Greg; Pack, Allan I.; Schwab, Richard J.

2014-01-01

Objectives: Accumulating evidence has shown that there is a genetic contribution to obstructive sleep apnea (OSA).The objectives were to use magnetic resonance imaging (MRI) cephalometry to (1) confirm heritability of craniofacial risk factors for OSA previously shown by cephalometrics; and (2) examine the heritability of new craniofacial structures that are measurable with MRI. Design: A sib pair “quad” design examining apneics, apneic siblings, controls, and control siblings. The study design used exact matching on ethnicity and sex, frequency matching on age, and statistical control for differences in age, sex, ethnicity, height, and weight. Setting: Academic medical center. Patients: We examined 55 apneic probands (apnea-hypopnea index [AHI]: 46.8 ± 33.5 events/h), 55 proband siblings (AHI: 11.1 ± 15.9 events/h), 55 controls (AHI: 2.2 ± 1.7 events/h), and 55 control siblings (AHI: 4.1 ± 4.0 events/h). Interventions: N/A. Measurements and Results: Five independent domains reflecting different aspects of the craniofacial structure were examined. We confirmed heritability of sella–nasion–subspinale (38%, P = 0.002), saddle angle (55%, P < 0.0001), mandibular length (24%, P = 0.02) and lower facial height (33%, P = 0.006) previously measured by cephalometry. In addition, the current study added new insights by demonstrating significant heritability of mandibular width (30%, P = 0.005), maxillary width (47%, P < 0.0001), distance from the hyoid bone to the retropogonion (36%, P = 0.0018) and size of the oropharyngeal space (31%, P = 0.004). Finally, our data indicate that heritability of the craniofacial structures is similar in normal patients and those with apnea. Conclusions: The data support our a priori hypothesis that the craniofacial structures that have been associated with obstructive sleep apnea (OSA) are heritable. We have demonstrated heritability for several intermediate craniofacial phenotypes for OSA. Thus, we believe that future studies should be able to identify genes associated with these intermediate craniofacial phenotypes. Citation: Chi L, Comyn FL, Keenan BT, Cater J, Maislin G, Pack AI, Schwab RJ. Heritability of craniofacial structures in normal subjects and patients with sleep apnea. SLEEP 2014;37(10):1689-1698. PMID:25197806

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

PubMed

Sampson, Joshua N; Wheeler, William A; Yeager, Meredith; Panagiotou, Orestis; Wang, Zhaoming; Berndt, Sonja I; Lan, Qing; Abnet, Christian C; Amundadottir, Laufey T; Figueroa, Jonine D; Landi, Maria Teresa; Mirabello, Lisa; Savage, Sharon A; Taylor, Philip R; De Vivo, Immaculata; McGlynn, Katherine A; Purdue, Mark P; Rajaraman, Preetha; Adami, Hans-Olov; Ahlbom, Anders; Albanes, Demetrius; Amary, Maria Fernanda; An, She-Juan; Andersson, Ulrika; Andriole, Gerald; Andrulis, Irene L; Angelucci, Emanuele; Ansell, Stephen M; Arici, Cecilia; Armstrong, Bruce K; Arslan, Alan A; Austin, Melissa A; Baris, Dalsu; Barkauskas, Donald A; Bassig, Bryan A; Becker, Nikolaus; Benavente, Yolanda; Benhamou, Simone; Berg, Christine; Van Den Berg, David; Bernstein, Leslie; Bertrand, Kimberly A; Birmann, Brenda M; Black, Amanda; Boeing, Heiner; Boffetta, Paolo; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Brinton, Louise; Brooks-Wilson, Angela R; Bueno-de-Mesquita, H Bas; Burdett, Laurie; Buring, Julie; Butler, Mary Ann; Cai, Qiuyin; Cancel-Tassin, Geraldine; Canzian, Federico; Carrato, Alfredo; Carreon, Tania; Carta, Angela; Chan, John K C; Chang, Ellen T; Chang, Gee-Chen; Chang, I-Shou; Chang, Jiang; Chang-Claude, Jenny; Chen, Chien-Jen; Chen, Chih-Yi; Chen, Chu; Chen, Chung-Hsing; Chen, Constance; Chen, Hongyan; Chen, Kexin; Chen, Kuan-Yu; Chen, Kun-Chieh; Chen, Ying; Chen, Ying-Hsiang; Chen, Yi-Song; Chen, Yuh-Min; Chien, Li-Hsin; Chirlaque, María-Dolores; Choi, Jin Eun; Choi, Yi Young; Chow, Wong-Ho; Chung, Charles C; Clavel, Jacqueline; Clavel-Chapelon, Françoise; Cocco, Pierluigi; Colt, Joanne S; Comperat, Eva; Conde, Lucia; Connors, Joseph M; Conti, David; Cortessis, Victoria K; Cotterchio, Michelle; Cozen, Wendy; Crouch, Simon; Crous-Bou, Marta; Cussenot, Olivier; Davis, Faith G; Ding, Ti; Diver, W Ryan; Dorronsoro, Miren; Dossus, Laure; Duell, Eric J; Ennas, Maria Grazia; Erickson, Ralph L; Feychting, Maria; Flanagan, Adrienne M; Foretova, Lenka; Fraumeni, Joseph F; Freedman, Neal D; Beane Freeman, Laura E; Fuchs, Charles; Gago-Dominguez, Manuela; Gallinger, Steven; Gao, Yu-Tang; Gapstur, Susan M; Garcia-Closas, Montserrat; García-Closas, Reina; Gascoyne, Randy D; Gastier-Foster, Julie; Gaudet, Mia M; Gaziano, J Michael; Giffen, Carol; Giles, Graham G; Giovannucci, Edward; Glimelius, Bengt; Goggins, Michael; Gokgoz, Nalan; Goldstein, Alisa M; Gorlick, Richard; Gross, Myron; Grubb, Robert; Gu, Jian; Guan, Peng; Gunter, Marc; Guo, Huan; Habermann, Thomas M; Haiman, Christopher A; Halai, Dina; Hallmans, Goran; Hassan, Manal; Hattinger, Claudia; He, Qincheng; He, Xingzhou; Helzlsouer, Kathy; Henderson, Brian; Henriksson, Roger; Hjalgrim, Henrik; Hoffman-Bolton, Judith; Hohensee, Chancellor; Holford, Theodore R; Holly, Elizabeth A; Hong, Yun-Chul; Hoover, Robert N; Horn-Ross, Pamela L; Hosain, G M Monawar; Hosgood, H Dean; Hsiao, Chin-Fu; Hu, Nan; Hu, Wei; Hu, Zhibin; Huang, Ming-Shyan; Huerta, Jose-Maria; Hung, Jen-Yu; Hutchinson, Amy; Inskip, Peter D; Jackson, Rebecca D; Jacobs, Eric J; Jenab, Mazda; Jeon, Hyo-Sung; Ji, Bu-Tian; Jin, Guangfu; Jin, Li; Johansen, Christoffer; Johnson, Alison; Jung, Yoo Jin; Kaaks, Rudolph; Kamineni, Aruna; Kane, Eleanor; Kang, Chang Hyun; Karagas, Margaret R; Kelly, Rachel S; Khaw, Kay-Tee; Kim, Christopher; Kim, Hee Nam; Kim, Jin Hee; Kim, Jun Suk; Kim, Yeul Hong; Kim, Young Tae; Kim, Young-Chul; Kitahara, Cari M; Klein, Alison P; Klein, Robert J; Kogevinas, Manolis; Kohno, Takashi; Kolonel, Laurence N; Kooperberg, Charles; Kricker, Anne; Krogh, Vittorio; Kunitoh, Hideo; Kurtz, Robert C; Kweon, Sun-Seog; LaCroix, Andrea; Lawrence, Charles; Lecanda, Fernando; Lee, Victor Ho Fun; Li, Donghui; Li, Haixin; Li, Jihua; Li, Yao-Jen; Li, Yuqing; Liao, Linda M; Liebow, Mark; Lightfoot, Tracy; Lim, Wei-Yen; Lin, Chien-Chung; Lin, Dongxin; Lindstrom, Sara; Linet, Martha S; Link, Brian K; Liu, Chenwei; Liu, Jianjun; Liu, Li; Ljungberg, Börje; Lloreta, Josep; Di Lollo, Simonetta; Lu, Daru; Lund, Eiluv; Malats, Nuria; Mannisto, Satu; Le Marchand, Loic; Marina, Neyssa; Masala, Giovanna; Mastrangelo, Giuseppe; Matsuo, Keitaro; Maynadie, Marc; McKay, James; McKean-Cowdin, Roberta; Melbye, Mads; Melin, Beatrice S; Michaud, Dominique S; Mitsudomi, Tetsuya; Monnereau, Alain; Montalvan, Rebecca; Moore, Lee E; Mortensen, Lotte Maxild; Nieters, Alexandra; North, Kari E; Novak, Anne J; Oberg, Ann L; Offit, Kenneth; Oh, In-Jae; Olson, Sara H; Palli, Domenico; Pao, William; Park, In Kyu; Park, Jae Yong; Park, Kyong Hwa; Patiño-Garcia, Ana; Pavanello, Sofia; Peeters, Petra H M; Perng, Reury-Perng; Peters, Ulrike; Petersen, Gloria M; Picci, Piero; Pike, Malcolm C; Porru, Stefano; Prescott, Jennifer; Prokunina-Olsson, Ludmila; Qian, Biyun; Qiao, You-Lin; Rais, Marco; Riboli, Elio; Riby, Jacques; Risch, Harvey A; Rizzato, Cosmeri; Rodabough, Rebecca; Roman, Eve; Roupret, Morgan; Ruder, Avima M; Sanjose, Silvia de; Scelo, Ghislaine; Schned, Alan; Schumacher, Fredrick; Schwartz, Kendra; Schwenn, Molly; Scotlandi, Katia; Seow, Adeline; Serra, Consol; Serra, Massimo; Sesso, Howard D; Setiawan, Veronica Wendy; Severi, Gianluca; Severson, Richard K; Shanafelt, Tait D; Shen, Hongbing; Shen, Wei; Shin, Min-Ho; Shiraishi, Kouya; Shu, Xiao-Ou; Siddiq, Afshan; Sierrasesúmaga, Luis; Sihoe, Alan Dart Loon; Skibola, Christine F; Smith, Alex; Smith, Martyn T; Southey, Melissa C; Spinelli, John J; Staines, Anthony; Stampfer, Meir; Stern, Marianna C; Stevens, Victoria L; Stolzenberg-Solomon, Rachael S; Su, Jian; Su, Wu-Chou; Sund, Malin; Sung, Jae Sook; Sung, Sook Whan; Tan, Wen; Tang, Wei; Tardón, Adonina; Thomas, David; Thompson, Carrie A; Tinker, Lesley F; Tirabosco, Roberto; Tjønneland, Anne; Travis, Ruth C; Trichopoulos, Dimitrios; Tsai, Fang-Yu; Tsai, Ying-Huang; Tucker, Margaret; Turner, Jenny; Vajdic, Claire M; Vermeulen, Roel C H; Villano, Danylo J; Vineis, Paolo; Virtamo, Jarmo; Visvanathan, Kala; Wactawski-Wende, Jean; Wang, Chaoyu; Wang, Chih-Liang; Wang, Jiu-Cun; Wang, Junwen; Wei, Fusheng; Weiderpass, Elisabete; Weiner, George J; Weinstein, Stephanie; Wentzensen, Nicolas; White, Emily; Witzig, Thomas E; Wolpin, Brian M; Wong, Maria Pik; Wu, Chen; Wu, Guoping; Wu, Junjie; Wu, Tangchun; Wu, Wei; Wu, Xifeng; Wu, Yi-Long; Wunder, Jay S; Xiang, Yong-Bing; Xu, Jun; Xu, Ping; Yang, Pan-Chyr; Yang, Tsung-Ying; Ye, Yuanqing; Yin, Zhihua; Yokota, Jun; Yoon, Ho-Il; Yu, Chong-Jen; Yu, Herbert; Yu, Kai; Yuan, Jian-Min; Zelenetz, Andrew; Zeleniuch-Jacquotte, Anne; Zhang, Xu-Chao; Zhang, Yawei; Zhao, Xueying; Zhao, Zhenhong; Zheng, Hong; Zheng, Tongzhang; Zheng, Wei; Zhou, Baosen; Zhu, Meng; Zucca, Mariagrazia; Boca, Simina M; Cerhan, James R; Ferri, Giovanni M; Hartge, Patricia; Hsiung, Chao Agnes; Magnani, Corrado; Miligi, Lucia; Morton, Lindsay M; Smedby, Karin E; Teras, Lauren R; Vijai, Joseph; Wang, Sophia S; Brennan, Paul; Caporaso, Neil E; Hunter, David J; Kraft, Peter; Rothman, Nathaniel; Silverman, Debra T; Slager, Susan L; Chanock, Stephen J; Chatterjee, Nilanjan

2015-12-01

Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Overcoming an obstacle in expanding a UMLS semantic type extent.

PubMed

Chen, Yan; Gu, Huanying; Perl, Yehoshua; Geller, James

2012-02-01

This paper strives to overcome a major problem encountered by a previous expansion methodology for discovering concepts highly likely to be missing a specific semantic type assignment in the UMLS. This methodology is the basis for an algorithm that presents the discovered concepts to a human auditor for review and possible correction. We analyzed the problem of the previous expansion methodology and discovered that it was due to an obstacle constituted by one or more concepts assigned the UMLS Semantic Network semantic type Classification. A new methodology was designed that bypasses such an obstacle without a combinatorial explosion in the number of concepts presented to the human auditor for review. The new expansion methodology with obstacle avoidance was tested with the semantic type Experimental Model of Disease and found over 500 concepts missed by the previous methodology that are in need of this semantic type assignment. Furthermore, other semantic types suffering from the same major problem were discovered, indicating that the methodology is of more general applicability. The algorithmic discovery of concepts that are likely missing a semantic type assignment is possible even in the face of obstacles, without an explosion in the number of processed concepts. Copyright © 2011 Elsevier Inc. All rights reserved.

Overcoming an Obstacle in Expanding a UMLS Semantic Type Extent

PubMed Central

Chen, Yan; Gu, Huanying; Perl, Yehoshua; Geller, James

2011-01-01

This paper strives to overcome a major problem encountered by a previous expansion methodology for discovering concepts highly likely to be missing a specific semantic type assignment in the UMLS. This methodology is the basis for an algorithm that presents the discovered concepts to a human auditor for review and possible correction. We analyzed the problem of the previous expansion methodology and discovered that it was due to an obstacle constituted by one or more concepts assigned the UMLS Semantic Network semantic type Classification. A new methodology was designed that bypasses such an obstacle without a combinatorial explosion in the number of concepts presented to the human auditor for review. The new expansion methodology with obstacle avoidance was tested with the semantic type Experimental Model of Disease and found over 500 concepts missed by the previous methodology that are in need of this semantic type assignment. Furthermore, other semantic types suffering from the same major problem were discovered, indicating that the methodology is of more general applicability. The algorithmic discovery of concepts that are likely missing a semantic type assignment is possible even in the face of obstacles, without an explosion in the number of processed concepts. PMID:21925287

Plumage condition in laying hens: genetic parameters for direct and indirect effects in two purebred layer lines.

PubMed

Brinker, Tessa; Bijma, Piter; Visscher, Jeroen; Rodenburg, T Bas; Ellen, Esther D

2014-05-29

Feather pecking is a major welfare issue in laying hen industry that leads to mortality. Due to a ban on conventional cages in the EU and on beak trimming in some countries of the EU, feather pecking will become an even bigger problem. Its severity depends both on the victim receiving pecking and on its group mates inflicting pecking (indirect effects), which together determine plumage condition of the victim. Plumage condition may depend, therefore, on both the direct genetic effect of an individual itself and on the indirect genetic effects of its group mates. Here, we present estimated genetic parameters for direct and indirect effects on plumage condition of different body regions in two purebred layer lines, and estimates of genetic correlations between body regions. Feather condition scores (FCS) were recorded at 40 weeks of age for neck, back, rump and belly and these four scores were added-up into a total FCS. A classical animal model and a direct-indirect effects model were used to estimate genetic parameters for FCS. In addition, a bivariate model with mortality (0/1) was used to account for mortality before recording FCS. Due to mortality during the first 23 weeks of laying, 5363 (for W1) and 5089 (for WB) FCS records were available. Total heritable variance for FCS ranged from 1.5% to 9.8% and from 9.8% to 53.6% when estimated respectively with the classical animal and the direct-indirect effects model. The direct-indirect effects model had a significantly higher likelihood. In both lines, 70% to 94% of the estimated total heritable variation in FCS was due to indirect effects. Using bivariate analysis of FCS and mortality did not affect estimates of genetic parameters. Genetic correlations were high between adjacent regions for FCS on neck, back, and rump but moderate to low for belly with other regions. Our results show that 70% to 94% of the heritable variation in FCS relates to indirect effects, indicating that methods of genetic selection that include indirect genetic effects offer perspectives to improve plumage condition in laying hens. This, in turn could reduce a major welfare problem.

Fidelity of Problem Solving in Everyday Practice: Typical Training May Miss the Mark

ERIC Educational Resources Information Center

Ruby, Susan F.; Crosby-Cooper, Tricia; Vanderwood, Michael L.

2011-01-01

With national attention on scaling up the implementation of Response to Intervention, problem solving teams remain one of the central components for development, implementation, and monitoring of school-based interventions. Studies have shown that problem solving teams evidence a sound theoretical base and demonstrated efficacy; however, limited…

Preservice Middle and High School Mathematics Teachers' Strategies When Solving Proportion Problems

ERIC Educational Resources Information Center

Arican, Muhammet

2018-01-01

The purpose of this study was to investigate eight preservice middle and high school mathematics teachers' solution strategies when solving single and multiple proportion problems. Real-world missing-value word problems were used in an interview setting to collect information about preservice teachers' (PSTs) reasoning about proportional…

Heritability of hair whorl position on the forehead in Konik horses.

PubMed

Górecka, A; Słoniewski, K; Golonka, M; Jaworski, Z; Jezierski, T

2006-12-01

There are studies on the relationship between the position and shape of hair whorls on bovine forehead and phenotypic traits. According to anecdotal beliefs by horse users and handlers, temperamental traits may be related to the position of hair whorls in horses. No previous research on the mechanisms of inheritance of hair whorls has been performed, so the aim of the present study was to determine the heritability of the position of the hair whorl on the forehead of Konik horses. The horses (n = 362) were classified into five groups based on the whorl position on forehead with respect to the top and bottom eye lines. The estimated heritability of hair whorl position was 0.753 (SE = 0.056). Heritability adjusted for the discontinuity of the trait was 0.836. The results show that hair whorl position in Konik Polski horses is highly heritable. The possible relationship between position of hair whorls on the forehead and other morphological traits needs further research and should be interpreted with caution.

Parental Divorce and Disordered Eating: An Investigation of a Gene-Environment Interaction

PubMed Central

Suisman, Jessica Lynn; Burt, S. Alexandra; McGue, Matt; Iacono, William G.; Klump, Kelly L.

2010-01-01

Objective We investigated gene-environment interactions (G×E) for associations between parental divorce and disordered eating (DE). Method Participants were 1,810 female twins from the Michigan State University Twin Registry and the Minnesota Twin Family Study. The Minnesota Eating Behaviors Survey was used to assess DE. We tested for G×E by comparing the heritability of DE in twins from divorced versus intact families. It was hypothesized that divorce would moderate the heritability of DE, in that heritability would be higher in twins from divorced than twins from intact families. Results As expected, the heritability of body dissatisfaction was significantly higher in twins from divorced than intact families. However, genetic influences were equal in twins from divorced and intact families for all other forms of DE. Discussion Although divorce did not moderate heritability of most DE symptoms, future research should replicate G×Es for body dissatisfaction and identify factors underlying this unique relationship. PMID:21312202

Parental divorce and disordered eating: an investigation of a gene-environment interaction.

PubMed

Suisman, Jessica L; Burt, S Alexandra; McGue, Matt; Iacono, William G; Klump, Kelly L

2011-03-01

We investigated gene-environment interactions (GxE) for associations between parental divorce and disordered eating (DE). Participants were 1,810 female twins from the Michigan State University Twin Registry and the Minnesota Twin Family Study. The Minnesota Eating Behaviors Survey was used to assess DE. We tested for GxE by comparing the heritability of DE in twins from divorced versus intact families. It was hypothesized that divorce would moderate the heritability of DE, in that heritability would be higher in twins from divorced than twins from intact families. As expected, the heritability of body dissatisfaction was significantly higher in twins from divorced than intact families. However, genetic influences were equal in twins from divorced and intact families for all other forms of DE. Although divorce did not moderate heritability of most DE symptoms, future research should replicate GxEs for body dissatisfaction and identify factors underlying this unique relationship. Copyright © 2010 Wiley Periodicals, Inc.

Exoatmospheric intercepts using zero effort miss steering for midcourse guidance

NASA Astrophysics Data System (ADS)

Newman, Brett

The suitability of proportional navigation, or an equivalent zero effort miss formulation, for exatmospheric intercepts during midcourse guidance, followed by a ballistic coast to the endgame, is addressed. The problem is formulated in terms of relative motion in a general, three dimensional framework. The proposed guidance law for the commanded thrust vector orientation consists of the sum of two terms: (1) along the line of sight unit direction and (2) along the zero effort miss component perpendicular to the line of sight and proportional to the miss itself and a guidance gain. If the guidance law is to be suitable for longer range targeting applications with significant ballistic coasting after burnout, determination of the zero effort miss must account for the different gravitational accelerations experienced by each vehicle. The proposed miss determination techniques employ approximations for the true differential gravity effect and thus, are less accurate than a direct numerical propagation of the governing equations, but more accurate than a baseline determination, which assumes equal accelerations for both vehicles. Approximations considered are constant, linear, quadratic, and linearized inverse square models. Theoretical results are applied to a numerical engagement scenario and the resulting performance is evaluated in terms of the miss distances determined from nonlinear simulation.

Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases.

PubMed

George, Rani; Kovak, Karen; Cox, Summer L

2015-06-01

Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

Egg shell quality in Japanese quail: characteristics, heritabilities and genetic and phenotypic relationships.

PubMed

Narinc, D; Aygun, A; Karaman, E; Aksoy, T

2015-07-01

The objective of the present study was to estimate heritabilities as well as genetic and phenotypic correlations for egg weight, specific gravity, shape index, shell ratio, egg shell strength, egg length, egg width and shell weight in Japanese quail eggs. External egg quality traits were measured on 5864 eggs of 934 female quails from a dam line selected for two generations. Within the Bayesian framework, using Gibbs Sampling algorithm, a multivariate animal model was applied to estimate heritabilities and genetic correlations for external egg quality traits. The heritability estimates for external egg quality traits were moderate to high and ranged from 0.29 to 0.81. The heritability estimates for egg and shell weight of 0.81 and 0.76 were fairly high. The genetic and phenotypic correlations between egg shell strength with specific gravity, shell ratio and shell weight ranging from 0.55 to 0.79 were relatively high. It can be concluded that it is possible to determine egg shell quality using the egg specific gravity values utilizing its high heritability and fairly high positive correlation with most of the egg shell quality traits. As a result, egg specific gravity may be the choice of selection criterion rather than other external egg traits for genetic improvement of egg shell quality in Japanese quails.

Evidence for higher heritability of somatotype compared to body mass index in female twins.

PubMed

Reis, Victor Machado; Machado, João V; Fortes, Marcos S; Fernandes, Paula Roquetti; Silva, António José; Dantas, Paulo Silva; Filho, José Fernandes

2007-01-01

The influence of genetics on human physique and obesity has been addressed by the literature. Evidence for heritability of anthropometric characteristics has been previously described, mainly for the body mass index (BMI). However, few studies have investigated the influence of genetics on the Heath-Carter somatotype. The aim of the present study was to assess the heritability of BMI and somatotype (endomorphy, mesomorphy, and ectomorphy) in a group of female monozygotic and dizygotic twins from childhood to early adulthood. A total of 28 females aged from 7 to 19 years old were studied. The group included 5 monozygotic and 9 dizygotic pairs of twins. The heritability was assessed by the twin method (h(2)). The anthropometric measures and somatotype were assessed using standard validated procedures. Significant differences between monozygotic and dizygotic pairs of twins were found for height, endomorphy, ectomorphy, and mesomorphy, and the heritability for these measures was high (h(2) between 0.88 and 0.97). No significant differences were found between monozygotic and dizygotic twins for weight, and the BMI and the heritability indexes were lower for these measures (respectively 0.42 and 0.52). The results of the present study have indicated that the somatotype may be more sensible to genetic influences than the BMI in females.

Heritability of female extra-pair paternity rate in song sparrows (Melospiza melodia)

PubMed Central

Reid, Jane M.; Arcese, Peter; Sardell, Rebecca J.; Keller, Lukas F.

2011-01-01

The forces driving the evolution of extra-pair reproduction in socially monogamous animals remain widely debated and unresolved. One key hypothesis is that female extra-pair reproduction evolves through indirect genetic benefits, reflecting increased additive genetic value of extra-pair offspring. Such evolution requires that a female's propensity to produce offspring that are sired by an extra-pair male is heritable. However, additive genetic variance and heritability in female extra-pair paternity (EPP) rate have not been quantified, precluding accurate estimation of the force of indirect selection. Sixteen years of comprehensive paternity and pedigree data from socially monogamous but genetically polygynandrous song sparrows (Melospiza melodia) showed significant additive genetic variance and heritability in the proportion of a female's offspring that was sired by an extra-pair male, constituting major components of the genetic architecture required for extra-pair reproduction to evolve through indirect additive genetic benefits. However, estimated heritabilities were moderately small (0.12 and 0.18 on the observed and underlying latent scales, respectively). The force of selection on extra-pair reproduction through indirect additive genetic benefits may consequently be relatively weak. However, the additive genetic variance and non-zero heritability observed in female EPP rate allow for multiple further genetic mechanisms to drive and constrain mating system evolution. PMID:20980302

Genetic and environmental contributions to cardiovascular disease risk in American Indians: the strong heart family study.

PubMed

North, Kari E; Howard, Barbara V; Welty, Thomas K; Best, Lyle G; Lee, Elisa T; Yeh, J L; Fabsitz, Richard R; Roman, Mary J; MacCluer, Jean W

2003-02-15

The aims of the Strong Heart Family Study are to clarify the genetic determinants of cardiovascular disease (CVD) risk in American Indians and to map and identify genes for CVD susceptibility. The authors describe the design of the Strong Heart Family Study (conducted between 1998 and 1999) and evaluate the heritabilities of CVD risk factors in American Indians from this study. In the first phase of the study, approximately 950 individuals, aged 18 years or more, in 32 extended families, were examined. The examination consisted of a personal interview, physical examination, laboratory tests, and an ultrasound examination of the carotid arteries. The phenotypes measured during the physical examination included anthropometry, lipoproteins, blood pressure, glycemic status, and clotting factors. Heritabilities for CVD risk factor phenotypes were estimated using a variance component approach and the program SOLAR. After accounting for the effects of covariates, the authors detected significant heritabilities for many CVD risk factor phenotypes (e.g., high density lipoprotein cholesterol (heritability = 0.50) and diastolic blood pressure (heritability = 0.34)). These results suggest that heredity explains a substantial proportion of the variability of CVD risk factors and that these heritabilities are large enough to warrant a search for major risk factor genes.

Keeping pace with climate change: what is wrong with the evolutionary potential of upper thermal limits?

PubMed Central

Santos, Mauro; Castañeda, Luis E; Rezende, Enrico L

2012-01-01

The potential of populations to evolve in response to ongoing climate change is partly conditioned by the presence of heritable genetic variation in relevant physiological traits. Recent research suggests that Drosophila melanogaster exhibits negligible heritability, hence little evolutionary potential in heat tolerance when measured under slow heating rates that presumably mimic conditions in nature. Here, we study the effects of directional selection for increased heat tolerance using Drosophila as a model system. We combine a physiological model to simulate thermal tolerance assays with multilocus models for quantitative traits. Our simulations show that, whereas the evolutionary response of the genetically determined upper thermal limit (CTmax) is independent of methodological context, the response in knockdown temperatures varies with measurement protocol and is substantially (up to 50%) lower than for CTmax. Realized heritabilities of knockdown temperature may grossly underestimate the true heritability of CTmax. For instance, assuming that the true heritability of CTmax in the base population is h2 = 0.25, realized heritabilities of knockdown temperature are around 0.08–0.16 depending on heating rate. These effects are higher in slow heating assays, suggesting that flawed methodology might explain the apparently limited evolutionary potential of cosmopolitan D. melanogaster. PMID:23170220

Study on miss distance based on projectile shock wave sensor

NASA Astrophysics Data System (ADS)

Gu, Guohua; Cheng, Gang; Zhang, Chenjun; Zhou, Lei

2017-05-01

The paper establishes miss distance models based on physical characteristic of shock-wave. The aerodynamic theory shows that the shock-wave of flying super-sonic projectile is generated for the projectile compressing and expending its ambient atmosphere. It advances getting miss distance according to interval of the first sensors, which first catches shock-wave, to solve the problem such as noise filtering on severe background, and signals of amplifier vibration dynamic disposal and electromagnetism compatibility, in order to improves the precision and reliability of gathering wave N signals. For the first time, it can identify the kinds of pills and firing units automatically, measure miss distance and azimuth when pills are firing. Application shows that the tactics and technique index is advanced all of the world.

[School absenteeism in Germany: prevalence of excused and unexcused absenteeism and its correlation with emotional and behavioural problems].

PubMed

Lenzen, Christoph; Fischer, Gloria; Jentzsch, Anika; Kaess, Michael; Parzer, Peter; Carli, Vladimir; Wasserman, Danuta; Resch, Franz; Brunner, Romuald

2013-01-01

Data about the prevalence of school absenteeism and its correlation with emotional and behavioural problems in Germany is scarce, in particular regarding excused absenteeism. This study aims to close the gap by examining a sample of 2,679 pupils attending the different types of secondary school (Hauptschule, Realschule, Gymnasium), who participated in a clinical trial for the prevention of truancy (WE-STAY-Project). Pupils' mean age was 14 years (M = 13.94, SD = 0.85, Range = 11-19) and gender distribution was balanced (49.35% males, 50.65% females). Using a self-report questionnaire, pupils where asked on how many days they had missed school on average per month during the last school year (excused and unexcused). Emotional and behavioural problems were measured by using the "Strengths and Difficulties Questionnaire" (SDQ). 4.1% of the pupils reported to have missed school without a valid excuse on more than four days per month (unexcused absenteeism). 6.1% had missed school having an excuse on more than ten days per month (excused absenteeism). Both, unexcused and excused absenteeism, showed an increase of emotional and behavioural problems dependent on the intensity of absenteeism. In conclusion, these findings show the relevance of school absenteeism in Germany. In the future, more attention should be given to pupils with also excused absenteeism.

Manifold regularized matrix completion for multi-label learning with ADMM.

PubMed

Liu, Bin; Li, Yingming; Xu, Zenglin

2018-05-01

Multi-label learning is a common machine learning problem arising from numerous real-world applications in diverse fields, e.g, natural language processing, bioinformatics, information retrieval and so on. Among various multi-label learning methods, the matrix completion approach has been regarded as a promising approach to transductive multi-label learning. By constructing a joint matrix comprising the feature matrix and the label matrix, the missing labels of test samples are regarded as missing values of the joint matrix. With the low-rank assumption of the constructed joint matrix, the missing labels can be recovered by minimizing its rank. Despite its success, most matrix completion based approaches ignore the smoothness assumption of unlabeled data, i.e., neighboring instances should also share a similar set of labels. Thus they may under exploit the intrinsic structures of data. In addition, the matrix completion problem can be less efficient. To this end, we propose to efficiently solve the multi-label learning problem as an enhanced matrix completion model with manifold regularization, where the graph Laplacian is used to ensure the label smoothness over it. To speed up the convergence of our model, we develop an efficient iterative algorithm, which solves the resulted nuclear norm minimization problem with the alternating direction method of multipliers (ADMM). Experiments on both synthetic and real-world data have shown the promising results of the proposed approach. Copyright © 2018 Elsevier Ltd. All rights reserved.

Heritability of myopia and ocular biometrics in Koreans: the healthy twin study.

PubMed

Kim, Myung Hun; Zhao, Di; Kim, Woori; Lim, Dong-Hui; Song, Yun-Mi; Guallar, Eliseo; Cho, Juhee; Sung, Joohon; Chung, Eui-Sang; Chung, Tae-Young

2013-05-01

To estimate the heritabilities of myopia and ocular biometrics among different family types among a Korean population. We studied 1508 adults in the Healthy Twin Study. Spherical equivalent, axial length, anterior chamber depth, and corneal astigmatism were measured by refraction, corneal topography, and A-scan ultrasonography. To see the degree of resemblance among different types of family relationships, intraclass correlation coefficients (ICC) were calculated. Variance-component methods were applied to estimate the genetic contributions to eye phenotypes as heritability based on the maximum likelihood estimation. Narrow sense heritability was calculated as the proportion of the total phenotypic variance explained by additive genetic effects, and linear and nonlinear effects of age, sex, and interactions between age and sex were adjusted. A total of 240 monozygotic twin pairs, 45 dizygotic twin pairs, and 938 singleton adult family members who were first-degree relatives of twins in 345 families were included in the study. ICCs for spherical equivalent from monozygotic twins, pooled first-degree pairs, and spouse pairs were 0.83, 0.34, and 0.20, respectively. The ICCs of other ocular biometrics were also significantly higher in monozygotic twins compared with other relative pairs, with greater consistency and conformity. The estimated narrow sense heritability (95% confidence interval) was 0.78 (0.71-0.84) for spherical equivalent; 0.86 (0.82-0.90) for axial length; 0.83 (0.76-0.91) for anterior chamber depth; and 0.70 (0.63-0.77) for corneal astigmatism. The estimated heritability of spherical equivalent and ocular biometrics in the Korean population suggests the compelling evidence that all traits are highly heritable.

Narrow-sense heritability estimation of complex traits using identity-by-descent information.

PubMed

Evans, Luke M; Tahmasbi, Rasool; Jones, Matt; Vrieze, Scott I; Abecasis, Gonçalo R; Das, Sayantan; Bjelland, Douglas W; de Candia, Teresa R; Yang, Jian; Goddard, Michael E; Visscher, Peter M; Keller, Matthew C

2018-03-28

Heritability is a fundamental parameter in genetics. Traditional estimates based on family or twin studies can be biased due to shared environmental or non-additive genetic variance. Alternatively, those based on genotyped or imputed variants typically underestimate narrow-sense heritability contributed by rare or otherwise poorly tagged causal variants. Identical-by-descent (IBD) segments of the genome share all variants between pairs of chromosomes except new mutations that have arisen since the last common ancestor. Therefore, relating phenotypic similarity to degree of IBD sharing among classically unrelated individuals is an appealing approach to estimating the near full additive genetic variance while possibly avoiding biases that can occur when modeling close relatives. We applied an IBD-based approach (GREML-IBD) to estimate heritability in unrelated individuals using phenotypic simulation with thousands of whole-genome sequences across a range of stratification, polygenicity levels, and the minor allele frequencies of causal variants (CVs). In simulations, the IBD-based approach produced unbiased heritability estimates, even when CVs were extremely rare, although precision was low. However, population stratification and non-genetic familial environmental effects shared across generations led to strong biases in IBD-based heritability. We used data on two traits in ~120,000 people from the UK Biobank to demonstrate that, depending on the trait and possible confounding environmental effects, GREML-IBD can be applied to very large genetic datasets to infer the contribution of very rare variants lost using other methods. However, we observed apparent biases in these real data, suggesting that more work may be required to understand and mitigate factors that influence IBD-based heritability estimates.

Heritability, parental transmission and environment correlation of pediatric-onset type 2 diabetes mellitus and metabolic syndrome-related traits.

PubMed

Miranda-Lora, América L; Vilchis-Gil, Jenny; Molina-Díaz, Mario; Flores-Huerta, Samuel; Klünder-Klünder, Miguel

2017-04-01

To estimate the heritability, parental transmission and environmental contributions to the phenotypic variation in type 2 diabetes mellitus and metabolic syndrome-related traits in families of Mexican children and adolescents. We performed a cross-sectional study of 184 tri-generational pedigrees with a total of 1160 individuals (99 families with a type 2 diabetes mellitus proband before age 19). The family history of type 2 diabetes mellitus in three generations was obtained by interview. Demographic, anthropometric, biochemical and lifestyle information was corroborated in parents and offspring. We obtained correlations for metabolic traits between relative pairs, and variance component methods were used to determine the heritability and environmental components. The heritability of early-onset of type 2 diabetes mellitus was 0.50 (p<1.0e-7). The heritability was greater than 0.5 for hypertension, hypoalphalipoproteinemia, hypercholesterolemia, body mass index, waist circumference, blood pressure, 2-h insulin, and cholesterol (p<0.001). In contrast, we observed a high environmental correlation (>0.50) for blood pressure, HbA1c and HDL-cholesterol after multivariate adjustment (p<0.05). Several traits, such as type 2 diabetes mellitus and insulin resistance, were significantly correlated only through the mother and others, such as hypertriglyceridemia, were significantly correlated only through the father. This study demonstrates that type 2 diabetes mellitus and metabolic syndrome-related traits are highly heritable among Mexican children and adolescents. Furthermore, several cardiometabolic factors have strong heritability and/or high environmental contributions that highlight the complex architecture of these alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

Prevalence, associated factors and heritabilities of metabolic syndrome and its individual components in African Americans: the Jackson Heart Study

PubMed Central

Khan, Rumana J; Gebreab, Samson Y; Sims, Mario; Riestra, Pia; Xu, Ruihua; Davis, Sharon K

2015-01-01

Objective Both environmental and genetic factors play important roles in the development of metabolic syndrome (MetS). Studies about its associated factors and genetic contribution in African Americans (AA) are sparse. Our aim was to report the prevalence, associated factors and heritability estimates of MetS and its components in AA men and women. Participants and setting Data of this cross-sectional study come from a large community-based Jackson Heart Study (JHS). We analysed a total of 5227 participants, of whom 1636 from 281 families were part of a family study subset of JHS. Methods Participants were classified as having MetS according to the Adult Treatment Panel III criteria. Multiple logistic regression analysis was performed to isolate independently associated factors of MetS (n=5227). Heritability was estimated from the family study subset using variance component methods (n=1636). Results About 27% of men and 40% of women had MetS. For men, associated factors with having MetS were older age, lower physical activity, higher body mass index, and higher homocysteine and adiponectin levels (p<0.05 for all). For women, in addition to all these, lower education, current smoking and higher stress were also significant (p<0.05 for all). After adjusting for covariates, the heritability of MetS was 32% (p<0.001). Heritability ranged from 14 to 45% among its individual components. Relatively higher heritability was estimated for waist circumference (45%), high density lipoprotein-cholesterol (43%) and triglycerides (42%). Heritability of systolic blood pressure (BP), diastolic BP and fasting blood glucose was 16%, 15% and 14%, respectively. Conclusions Stress and low education were associated with having MetS in AA women, but not in men. Higher heritability estimates for lipids and waist circumference support the hypothesis of lipid metabolism playing a central role in the development of MetS and encourage additional efforts to identify the underlying susceptibility genes for this syndrome in AA. PMID:26525420

Genetic and environmental influences on skeletal muscle phenotypes as a function of age and sex in large, multigenerational families of African heritage.

PubMed

Prior, Steven J; Roth, Stephen M; Wang, Xiaojing; Kammerer, Candace; Miljkovic-Gacic, Iva; Bunker, Clareann H; Wheeler, Victor W; Patrick, Alan L; Zmuda, Joseph M

2007-10-01

The aim of this study was to estimate the heritability of and environmental contributions to skeletal muscle phenotypes (appendicular lean mass and calf muscle cross-sectional area) in subjects of African descent and to determine whether heritability estimates are impacted by sex or age. Body composition was measured by dual-energy X-ray absorptiometry and computed tomography in 444 men and women aged 18 yr and older (mean: 43 yr) from eight large, multigenerational Afro-Caribbean families (family size range: 21-112). Using quantitative genetic methods, we estimated heritability and the association of anthropometric, lifestyle, and medical variables with skeletal muscle phenotypes. In the overall group, we estimated the heritability of lean mass and calf muscle cross-sectional area (h(2) = 0.18-0.23, P < 0.01) and contribution of environmental factors to these phenotypes (r(2) = 0.27-0.55, P < 0.05). In our age-specific analysis, the heritability of leg lean mass was lower in older vs. younger individuals (h(2) = 0.05 vs. 0.23, respectively, P = 0.1). Sex was a significant covariate in our models (P < 0.001), although sex-specific differences in heritability varied depending on the lean mass phenotype analyzed. High genetic correlations (rho(G) = 0.69-0.81; P < 0.01) between different lean mass measures suggest these traits share a large proportion of genetic components. Our results demonstrate the heritability of skeletal muscle traits in individuals of African heritage and that heritability may differ as a function of sex and age. As the loss of skeletal muscle mass is related to metabolic abnormalities, disability, and mortality in older individuals, further research is warranted to identify specific genetic loci that contribute to these traits in general and in a sex- and age-specific manner.

Effect of Body Composition Methodology on Heritability Estimation of Body Fatness

PubMed Central

Elder, Sonya J.; Roberts, Susan B.; McCrory, Megan A.; Das, Sai Krupa; Fuss, Paul J.; Pittas, Anastassios G.; Greenberg, Andrew S.; Heymsfield, Steven B.; Dawson-Hughes, Bess; Bouchard, Thomas J.; Saltzman, Edward; Neale, Michael C.

2014-01-01

Heritability estimates of human body fatness vary widely and the contribution of body composition methodology to this variability is unknown. The effect of body composition methodology on estimations of genetic and environmental contributions to body fatness variation was examined in 78 adult male and female monozygotic twin pairs reared apart or together. Body composition was assessed by six methods – body mass index (BMI), dual energy x-ray absorptiometry (DXA), underwater weighing (UWW), total body water (TBW), bioelectric impedance (BIA), and skinfold thickness. Body fatness was expressed as percent body fat, fat mass, and fat mass/height2 to assess the effect of body fatness expression on heritability estimates. Model-fitting multivariate analyses were used to assess the genetic and environmental components of variance. Mean BMI was 24.5 kg/m2 (range of 17.8–43.4 kg/m2). There was a significant effect of body composition methodology (p<0.001) on heritability estimates, with UWW giving the highest estimate (69%) and BIA giving the lowest estimate (47%) for fat mass/height2. Expression of body fatness as percent body fat resulted in significantly higher heritability estimates (on average 10.3% higher) compared to expression as fat mass/height2 (p=0.015). DXA and TBW methods expressing body fatness as fat mass/height2 gave the least biased heritability assessments, based on the small contribution of specific genetic factors to their genetic variance. A model combining DXA and TBW methods resulted in a relatively low FM/ht2 heritability estimate of 60%, and significant contributions of common and unique environmental factors (22% and 18%, respectively). The body fatness heritability estimate of 60% indicates a smaller contribution of genetic variance to total variance than many previous studies using less powerful research designs have indicated. The results also highlight the importance of environmental factors and possibly genotype by environmental interactions in the etiology of weight gain and the obesity epidemic. PMID:25067962

Inferential precision in single-case time-series data streams: how well does the em procedure perform when missing observations occur in autocorrelated data?

PubMed

Smith, Justin D; Borckardt, Jeffrey J; Nash, Michael R

2012-09-01

The case-based time-series design is a viable methodology for treatment outcome research. However, the literature has not fully addressed the problem of missing observations with such autocorrelated data streams. Mainly, to what extent do missing observations compromise inference when observations are not independent? Do the available missing data replacement procedures preserve inferential integrity? Does the extent of autocorrelation matter? We use Monte Carlo simulation modeling of a single-subject intervention study to address these questions. We find power sensitivity to be within acceptable limits across four proportions of missing observations (10%, 20%, 30%, and 40%) when missing data are replaced using the Expectation-Maximization Algorithm, more commonly known as the EM Procedure (Dempster, Laird, & Rubin, 1977). This applies to data streams with lag-1 autocorrelation estimates under 0.80. As autocorrelation estimates approach 0.80, the replacement procedure yields an unacceptable power profile. The implications of these findings and directions for future research are discussed. Copyright © 2011. Published by Elsevier Ltd.

Recognition of facial emotion and affective prosody in children with ASD (+ADHD) and their unaffected siblings.

PubMed

Oerlemans, Anoek M; van der Meer, Jolanda M J; van Steijn, Daphne J; de Ruiter, Saskia W; de Bruijn, Yvette G E; de Sonneville, Leo M J; Buitelaar, Jan K; Rommelse, Nanda N J

2014-05-01

Autism is a highly heritable and clinically heterogeneous neuropsychiatric disorder that frequently co-occurs with other psychopathologies, such as attention-deficit/hyperactivity disorder (ADHD). An approach to parse heterogeneity is by forming more homogeneous subgroups of autism spectrum disorder (ASD) patients based on their underlying, heritable cognitive vulnerabilities (endophenotypes). Emotion recognition is a likely endophenotypic candidate for ASD and possibly for ADHD. Therefore, this study aimed to examine whether emotion recognition is a viable endophenotypic candidate for ASD and to assess the impact of comorbid ADHD in this context. A total of 90 children with ASD (43 with and 47 without ADHD), 79 ASD unaffected siblings, and 139 controls aged 6-13 years, were included to test recognition of facial emotion and affective prosody. Our results revealed that the recognition of both facial emotion and affective prosody was impaired in children with ASD and aggravated by the presence of ADHD. The latter could only be partly explained by typical ADHD cognitive deficits, such as inhibitory and attentional problems. The performance of unaffected siblings could overall be considered at an intermediate level, performing somewhat worse than the controls and better than the ASD probands. Our findings suggest that emotion recognition might be a viable endophenotype in ASD and a fruitful target in future family studies of the genetic contribution to ASD and comorbid ADHD. Furthermore, our results suggest that children with comorbid ASD and ADHD are at highest risk for emotion recognition problems.

Genetic Psychophysiology: advances, problems, and future directions

PubMed Central

Anokhin, Andrey P.

2014-01-01

This paper presents an overview of historical advances and the current state of genetic psychophysiology, a rapidly developing interdisciplinary research linking genetics, brain, and human behavior, discusses methodological problems, and outlines future directions of research. The main goals of genetic psychophysiology are to elucidate the neural pathways and mechanisms mediating genetic influences on cognition and emotion, identify intermediate brain-based phenotypes for psychopathology, and provide a functional characterization of genes being discovered by large association studies of behavioral phenotypes. Since the initiation of this neurogenetic approach to human individual differences in the 1970s, numerous twin and family studies have provided strong evidence for heritability of diverse aspects of brain function including resting-state brain oscillations, functional connectivity, and event-related neural activity in a variety of cognitive and emotion processing tasks, as well as peripheral psychophysiological responses. These data indicate large differences in the presence and strength of genetic influences across measures and domains, permitting the selection of heritable characteristics for gene finding studies. More recently, candidate gene association studies began to implicate specific genetic variants in different aspects of neurocognition. However, great caution is needed in pursuing this line of research due to its demonstrated proneness to generate false-positive findings. Recent developments in methods for physiological signal analysis, hemodynamic imaging, and genomic technologies offer new exciting opportunities for the investigation of the interplay between genetic and environmental factors in the development of individual differences in behavior, both normal and abnormal. PMID:24739435

Magnitude of dental caries, missing and filled teeth in Malawi: National Oral Health Survey.

PubMed

Msyamboza, Kelias Phiri; Phale, Enock; Namalika, Jessie Mlotha; Mwase, Younam; Samonte, Gian Carlo; Kajirime, Doubt; Sumani, Sewedi; Chalila, Pax D; Potani, Rennie; Mwale, George Chithope-; Kathyola, Damson; Mukiwa, Weston

2016-03-09

Oral health problems are significant cause of morbidity particularly in sub-Saharan Africa. In Malawi, routine health management information system data over the years showed that oral health problems were one of the top ten reasons for outpatient attendance. However, to date, no national oral survey has been carried out to determine the prevalence of oral health problems. A national population-based cross-sectional survey was conducted in 2013. A total of 130 enumeration areas (EAs) were randomly selected and from each EA, 40 participants were randomly selected as per WHO STEPS survey protocol. Eligible participants were 12, 15, 35-44 and 65-74 year old. A multi-stage sampling design was used to obtain a national representative sample of these age groups. Oral examination was based on WHO diagnostic criteria (2010). A total of 5400 participants were enrolled in the survey. Of these: 3304 (61.3 %) were females, 2090 (38.7 %) were males; 327 (6.9 %) were from urban and 4386 (93.1 %) from rural areas; 1115 (20.6 %), 993 (17.3 %), 2306 (42.7 %) and 683 (12.6 %) were aged 12, 15, 35-44, 65-74 years respectively. Among 12 year-old, 15 year-old, 35-44 and 65-74 year age groups, prevalence of dental caries was 19.1, 21.9, 49.0 and 49.2 % respectively, overall 37.4 %. Prevalence of missing teeth was 2.7, 5.2, 47.7 and 79.9 %, overall 35.2 %. Prevalence of filled teeth was 0.2 %, 1.3 %, 8.7 %, 12.7 %, overall 6.5 %. Prevalence of bleeding gums was 13.0, 11.8, 30.8 and 36.1 %, overall 23.5 %. Toothache, dental caries and missing teeth were more common in females than males; 46.5 % vs 37.9 %, 40.5 % vs 32.4 %, 37.7 % vs 30.1 % respectively, all p < 0.05. Prevalence of dental caries and missing teeth in urban areas were as high as in the rural areas; 33.3 % vs 37.4 % and 30.9 % vs 33.7 % respectively, all p > 0.05. The mean number of decayed, missing and filled teeth (DMFT) in 12, 15, 35-44, 65-74 year old was 0.67, 0.71, 3.11 and 6.87 respectively. Self- reported brushing of teeth was poor with only 35.2 % of people brushed their teeth twice a day and tobacco smoking was high, particularly among adult males where one in five (22.9 %) was a smoker. This study demonstrated that oral health problems are major public health problems in Malawi. One in five (21 %) adolescents aged 12-15 years and half (49 %) of adults aged 35 years or more had dental caries, half (48 %) and 80 % of the population aged 35-44, 65-74 years had missing teeth respectively. Toothache, dental caries and missing teeth were more prevalent in females than males and prevalence in urban was as high as in rural areas. Oral hygiene was poor with less than 40 % of the population brush their teeth twice a day and tobacco smoking was high, particularly in men where prevalence was 23 %. These findings could be used to develop evidence-informed national policy, action and resource mobilization plan and community based interventions to reduce the prevalence of oral health problems in Malawi.

Multiple imputation of missing fMRI data in whole brain analysis

PubMed Central

Vaden, Kenneth I.; Gebregziabher, Mulugeta; Kuchinsky, Stefanie E.; Eckert, Mark A.

2012-01-01

Whole brain fMRI analyses rarely include the entire brain because of missing data that result from data acquisition limits and susceptibility artifact, in particular. This missing data problem is typically addressed by omitting voxels from analysis, which may exclude brain regions that are of theoretical interest and increase the potential for Type II error at cortical boundaries or Type I error when spatial thresholds are used to establish significance. Imputation could significantly expand statistical map coverage, increase power, and enhance interpretations of fMRI results. We examined multiple imputation for group level analyses of missing fMRI data using methods that leverage the spatial information in fMRI datasets for both real and simulated data. Available case analysis, neighbor replacement, and regression based imputation approaches were compared in a general linear model framework to determine the extent to which these methods quantitatively (effect size) and qualitatively (spatial coverage) increased the sensitivity of group analyses. In both real and simulated data analysis, multiple imputation provided 1) variance that was most similar to estimates for voxels with no missing data, 2) fewer false positive errors in comparison to mean replacement, and 3) fewer false negative errors in comparison to available case analysis. Compared to the standard analysis approach of omitting voxels with missing data, imputation methods increased brain coverage in this study by 35% (from 33,323 to 45,071 voxels). In addition, multiple imputation increased the size of significant clusters by 58% and number of significant clusters across statistical thresholds, compared to the standard voxel omission approach. While neighbor replacement produced similar results, we recommend multiple imputation because it uses an informed sampling distribution to deal with missing data across subjects that can include neighbor values and other predictors. Multiple imputation is anticipated to be particularly useful for 1) large fMRI data sets with inconsistent missing voxels across subjects and 2) addressing the problem of increased artifact at ultra-high field, which significantly limit the extent of whole brain coverage and interpretations of results. PMID:22500925

A comparison of multiple imputation methods for handling missing values in longitudinal data in the presence of a time-varying covariate with a non-linear association with time: a simulation study.

PubMed

De Silva, Anurika Priyanjali; Moreno-Betancur, Margarita; De Livera, Alysha Madhu; Lee, Katherine Jane; Simpson, Julie Anne

2017-07-25

Missing data is a common problem in epidemiological studies, and is particularly prominent in longitudinal data, which involve multiple waves of data collection. Traditional multiple imputation (MI) methods (fully conditional specification (FCS) and multivariate normal imputation (MVNI)) treat repeated measurements of the same time-dependent variable as just another 'distinct' variable for imputation and therefore do not make the most of the longitudinal structure of the data. Only a few studies have explored extensions to the standard approaches to account for the temporal structure of longitudinal data. One suggestion is the two-fold fully conditional specification (two-fold FCS) algorithm, which restricts the imputation of a time-dependent variable to time blocks where the imputation model includes measurements taken at the specified and adjacent times. To date, no study has investigated the performance of two-fold FCS and standard MI methods for handling missing data in a time-varying covariate with a non-linear trajectory over time - a commonly encountered scenario in epidemiological studies. We simulated 1000 datasets of 5000 individuals based on the Longitudinal Study of Australian Children (LSAC). Three missing data mechanisms: missing completely at random (MCAR), and a weak and a strong missing at random (MAR) scenarios were used to impose missingness on body mass index (BMI) for age z-scores; a continuous time-varying exposure variable with a non-linear trajectory over time. We evaluated the performance of FCS, MVNI, and two-fold FCS for handling up to 50% of missing data when assessing the association between childhood obesity and sleep problems. The standard two-fold FCS produced slightly more biased and less precise estimates than FCS and MVNI. We observed slight improvements in bias and precision when using a time window width of two for the two-fold FCS algorithm compared to the standard width of one. We recommend the use of FCS or MVNI in a similar longitudinal setting, and when encountering convergence issues due to a large number of time points or variables with missing values, the two-fold FCS with exploration of a suitable time window.

Automating Web Collection and Validation of GPS data for Longitudinal Urban Travel Studies

DOT National Transportation Integrated Search

2012-08-01

Traditional paper and phone travel surveys are expensive, time consuming, and have problems of missing trips, illogical trip sequences, and : imprecise travel time. GPS-based travel surveys can avoid many of these problems and are becoming increasing...

Clustering and variable selection in the presence of mixed variable types and missing data.

PubMed

Storlie, C B; Myers, S M; Katusic, S K; Weaver, A L; Voigt, R G; Croarkin, P E; Stoeckel, R E; Port, J D

2018-05-17

We consider the problem of model-based clustering in the presence of many correlated, mixed continuous, and discrete variables, some of which may have missing values. Discrete variables are treated with a latent continuous variable approach, and the Dirichlet process is used to construct a mixture model with an unknown number of components. Variable selection is also performed to identify the variables that are most influential for determining cluster membership. The work is motivated by the need to cluster patients thought to potentially have autism spectrum disorder on the basis of many cognitive and/or behavioral test scores. There are a modest number of patients (486) in the data set along with many (55) test score variables (many of which are discrete valued and/or missing). The goal of the work is to (1) cluster these patients into similar groups to help identify those with similar clinical presentation and (2) identify a sparse subset of tests that inform the clusters in order to eliminate unnecessary testing. The proposed approach compares very favorably with other methods via simulation of problems of this type. The results of the autism spectrum disorder analysis suggested 3 clusters to be most likely, while only 4 test scores had high (>0.5) posterior probability of being informative. This will result in much more efficient and informative testing. The need to cluster observations on the basis of many correlated, continuous/discrete variables with missing values is a common problem in the health sciences as well as in many other disciplines. Copyright © 2018 John Wiley & Sons, Ltd.

A regressive methodology for estimating missing data in rainfall daily time series

NASA Astrophysics Data System (ADS)

Barca, E.; Passarella, G.

2009-04-01

The "presence" of gaps in environmental data time series represents a very common, but extremely critical problem, since it can produce biased results (Rubin, 1976). Missing data plagues almost all surveys. The problem is how to deal with missing data once it has been deemed impossible to recover the actual missing values. Apart from the amount of missing data, another issue which plays an important role in the choice of any recovery approach is the evaluation of "missingness" mechanisms. When data missing is conditioned by some other variable observed in the data set (Schafer, 1997) the mechanism is called MAR (Missing at Random). Otherwise, when the missingness mechanism depends on the actual value of the missing data, it is called NCAR (Not Missing at Random). This last is the most difficult condition to model. In the last decade interest arose in the estimation of missing data by using regression (single imputation). More recently multiple imputation has become also available, which returns a distribution of estimated values (Scheffer, 2002). In this paper an automatic methodology for estimating missing data is presented. In practice, given a gauging station affected by missing data (target station), the methodology checks the randomness of the missing data and classifies the "similarity" between the target station and the other gauging stations spread over the study area. Among different methods useful for defining the similarity degree, whose effectiveness strongly depends on the data distribution, the Spearman correlation coefficient was chosen. Once defined the similarity matrix, a suitable, nonparametric, univariate, and regressive method was applied in order to estimate missing data in the target station: the Theil method (Theil, 1950). Even though the methodology revealed to be rather reliable an improvement of the missing data estimation can be achieved by a generalization. A first possible improvement consists in extending the univariate technique to the multivariate approach. Another approach follows the paradigm of the "multiple imputation" (Rubin, 1987; Rubin, 1988), which consists in using a set of "similar stations" instead than the most similar. This way, a sort of estimation range can be determined allowing the introduction of uncertainty. Finally, time series can be grouped on the basis of monthly rainfall rates defining classes of wetness (i.e.: dry, moderately rainy and rainy), in order to achieve the estimation using homogeneous data subsets. We expect that integrating the methodology with these enhancements will certainly improve its reliability. The methodology was applied to the daily rainfall time series data registered in the Candelaro River Basin (Apulia - South Italy) from 1970 to 2001. REFERENCES D.B., Rubin, 1976. Inference and Missing Data. Biometrika 63 581-592 D.B. Rubin, 1987. Multiple Imputation for Nonresponce in Surveys, New York: John Wiley & Sons, Inc. D.B. Rubin, 1988. An overview of multiple imputation. In Survey Research Section, pp. 79-84, American Statistical Association, 1988. J.L., Schafer, 1997. Analysis of Incomplete Multivariate Data, Chapman & Hall. J., Scheffer, 2002. Dealing with Missing Data. Res. Lett. Inf. Math. Sci. 3, 153-160. Available online at http://www.massey.ac.nz/~wwiims/research/letters/ H. Theil, 1950. A rank-invariant method of linear and polynomial regression analysis. Indicationes Mathematicae, 12, pp.85-91.

Automatic Annotation Method on Learners' Opinions in Case Method Discussion

ERIC Educational Resources Information Center

Samejima, Masaki; Hisakane, Daichi; Komoda, Norihisa

2015-01-01

Purpose: The purpose of this paper is to annotate an attribute of a problem, a solution or no annotation on learners' opinions automatically for supporting the learners' discussion without a facilitator. The case method aims at discussing problems and solutions in a target case. However, the learners miss discussing some of problems and solutions.…

Students' Performance on Missing-Value Word Problems: A Cross-National Developmental Study

ERIC Educational Resources Information Center

Jiang, Ronghuan; Li, Xiaodong; Fernández, Ceneida; Fu, Xinchen

2017-01-01

This study investigates Spanish and Chinese students' performance on both addition problems and proportion problems considering a cross-national perspective. The effect of number structure and nature of quantities was also considered. Nine hundred twenty-five 4th to 8th graders (453 Chinese, 472 Spanish) took a test which is composed of addition…

Event-Based Variance-Constrained ${\\mathcal {H}}_{\\infty }$ Filtering for Stochastic Parameter Systems Over Sensor Networks With Successive Missing Measurements.

PubMed

Wang, Licheng; Wang, Zidong; Han, Qing-Long; Wei, Guoliang

2018-03-01

This paper is concerned with the distributed filtering problem for a class of discrete time-varying stochastic parameter systems with error variance constraints over a sensor network where the sensor outputs are subject to successive missing measurements. The phenomenon of the successive missing measurements for each sensor is modeled via a sequence of mutually independent random variables obeying the Bernoulli binary distribution law. To reduce the frequency of unnecessary data transmission and alleviate the communication burden, an event-triggered mechanism is introduced for the sensor node such that only some vitally important data is transmitted to its neighboring sensors when specific events occur. The objective of the problem addressed is to design a time-varying filter such that both the requirements and the variance constraints are guaranteed over a given finite-horizon against the random parameter matrices, successive missing measurements, and stochastic noises. By recurring to stochastic analysis techniques, sufficient conditions are established to ensure the existence of the time-varying filters whose gain matrices are then explicitly characterized in term of the solutions to a series of recursive matrix inequalities. A numerical simulation example is provided to illustrate the effectiveness of the developed event-triggered distributed filter design strategy.

Missing-value estimation using linear and non-linear regression with Bayesian gene selection.

PubMed

Zhou, Xiaobo; Wang, Xiaodong; Dougherty, Edward R

2003-11-22

Data from microarray experiments are usually in the form of large matrices of expression levels of genes under different experimental conditions. Owing to various reasons, there are frequently missing values. Estimating these missing values is important because they affect downstream analysis, such as clustering, classification and network design. Several methods of missing-value estimation are in use. The problem has two parts: (1) selection of genes for estimation and (2) design of an estimation rule. We propose Bayesian variable selection to obtain genes to be used for estimation, and employ both linear and nonlinear regression for the estimation rule itself. Fast implementation issues for these methods are discussed, including the use of QR decomposition for parameter estimation. The proposed methods are tested on data sets arising from hereditary breast cancer and small round blue-cell tumors. The results compare very favorably with currently used methods based on the normalized root-mean-square error. The appendix is available from http://gspsnap.tamu.edu/gspweb/zxb/missing_zxb/ (user: gspweb; passwd: gsplab).

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T-Cell Decline, and Per-Parasite Pathogenicity.

PubMed

Bertels, Frederic; Marzel, Alex; Leventhal, Gabriel; Mitov, Venelin; Fellay, Jacques; Günthard, Huldrych F; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Battegay, Manuel; Rauch, Andri; Cavassini, Matthias; Calmy, Alexandra; Bernasconi, Enos; Schmid, Patrick; Scherrer, Alexandra U; Müller, Viktor; Bonhoeffer, Sebastian; Kouyos, Roger; Regoes, Roland R

2018-01-01

Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as "per-parasite pathogenicity". Using viral load and CD4+ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence-measured as the rate of decline of CD4+ T cells-and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor-recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T-cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T-cell decline is 17% (5-30%), and that of the per-parasite pathogenicity is 17% (4-29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12-46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Dissecting HIV Virulence: Heritability of Setpoint Viral Load, CD4+ T-Cell Decline, and Per-Parasite Pathogenicity

PubMed Central

Bertels, Frederic; Marzel, Alex; Leventhal, Gabriel; Mitov, Venelin; Fellay, Jacques; Günthard, Huldrych F; Böni, Jürg; Yerly, Sabine; Klimkait, Thomas; Aubert, Vincent; Battegay, Manuel; Rauch, Andri; Cavassini, Matthias; Calmy, Alexandra; Bernasconi, Enos; Schmid, Patrick; Scherrer, Alexandra U; Müller, Viktor; Bonhoeffer, Sebastian; Kouyos, Roger; Regoes, Roland R

2018-01-01

Abstract Pathogen strains may differ in virulence because they attain different loads in their hosts, or because they induce different disease-causing mechanisms independent of their load. In evolutionary ecology, the latter is referred to as “per-parasite pathogenicity”. Using viral load and CD4+ T-cell measures from 2014 HIV-1 subtype B-infected individuals enrolled in the Swiss HIV Cohort Study, we investigated if virulence—measured as the rate of decline of CD4+ T cells—and per-parasite pathogenicity are heritable from donor to recipient. We estimated heritability by donor–recipient regressions applied to 196 previously identified transmission pairs, and by phylogenetic mixed models applied to a phylogenetic tree inferred from HIV pol sequences. Regressing the CD4+ T-cell declines and per-parasite pathogenicities of the transmission pairs did not yield heritability estimates significantly different from zero. With the phylogenetic mixed model, however, our best estimate for the heritability of the CD4+ T-cell decline is 17% (5–30%), and that of the per-parasite pathogenicity is 17% (4–29%). Further, we confirm that the set-point viral load is heritable, and estimate a heritability of 29% (12–46%). Interestingly, the pattern of evolution of all these traits differs significantly from neutrality, and is most consistent with stabilizing selection for the set-point viral load, and with directional selection for the CD4+ T-cell decline and the per-parasite pathogenicity. Our analysis shows that the viral genotype affects virulence mainly by modulating the per-parasite pathogenicity, while the indirect effect via the set-point viral load is minor. PMID:29029206

Estimates of genetic parameters for chemical traits of meat quality in Japanese black cattle

PubMed Central

Sakuma, Hironori; Saito, Kaoru; Kohira, Kimiko; Ohhashi, Fumie; Shoji, Noriaki

2016-01-01

Abstract Genetic parameters for 54 carcass and chemical traits, such as general composition (moisture, crude fat and crude protein), fatty acid composition and water‐soluble compounds (free amino acids, peptides, nucleotides and sugars) of 587 commercial Japanese Black cattle were assessed. Heritability estimates for carcass traits and general composition ranged between 0.19–0.28, whereas those for fatty acid composition ranged between 0.11–0.85. Most heritability estimates for water‐soluble compounds were lower than 0.30; these traits were affected by aging period. Moderate heritability was observed for glutamine, alanine, taurine, anserine, inosine 5′‐monophosphate (IMP), inosine and myo‐inositol. In particular, heritability estimates were the highest (0.66) for taurine. Traits with moderate heritability were unaffected by aging period, with the exception of IMP, which was affected by aging period but exhibited moderate heritability (0.47). Although phenotypic correlations of water‐soluble compounds with carcass weight (CW), beef marbling standard (BMS) and monounsaturated fatty acid were generally low, genetic correlations between these traits were low to high. At the genetic level, most of the water‐soluble compounds were positively correlated with monounsaturated fatty acid but negatively correlated with CW and BMS. Thus, our results indicate that genetic variance and correlations could exist and be captured for some of the water‐soluble compounds. PMID:27146072

Uncovering the hidden players in Lepidoptera biology: the heritable microbial endosymbionts.

PubMed

Duplouy, Anne; Hornett, Emily A

2018-01-01

The Lepidoptera is one of the most widespread and recognisable insect orders. Due to their remarkable diversity, economic and ecological importance, moths and butterflies have been studied extensively over the last 200 years. More recently, the relationship between Lepidoptera and their heritable microbial endosymbionts has received increasing attention. Heritable endosymbionts reside within the host's body and are often, but not exclusively, inherited through the female line. Advancements in molecular genetics have revealed that host-associated microbes are both extremely prevalent among arthropods and highly diverse. Furthermore, heritable endosymbionts have been repeatedly demonstrated to play an integral role in many aspects of host biology, particularly host reproduction. Here, we review the major findings of research of heritable microbial endosymbionts of butterflies and moths. We promote the Lepidoptera as important models in the study of reproductive manipulations employed by heritable endosymbionts, with the mechanisms underlying male-killing and feminisation currently being elucidated in moths and butterflies. We also reveal that the vast majority of research undertaken of Lepidopteran endosymbionts concerns Wolbachia . While this highly prevalent bacterium is undoubtedly important, studies should move towards investigating the presence of other, and interacting endosymbionts, and we discuss the merits of examining the microbiome of Lepidoptera to this end. We finally consider the importance of understanding the influence of endosymbionts under global environmental change and when planning conservation management of endangered Lepidoptera species.

Uncovering the hidden players in Lepidoptera biology: the heritable microbial endosymbionts

PubMed Central

2018-01-01

The Lepidoptera is one of the most widespread and recognisable insect orders. Due to their remarkable diversity, economic and ecological importance, moths and butterflies have been studied extensively over the last 200 years. More recently, the relationship between Lepidoptera and their heritable microbial endosymbionts has received increasing attention. Heritable endosymbionts reside within the host’s body and are often, but not exclusively, inherited through the female line. Advancements in molecular genetics have revealed that host-associated microbes are both extremely prevalent among arthropods and highly diverse. Furthermore, heritable endosymbionts have been repeatedly demonstrated to play an integral role in many aspects of host biology, particularly host reproduction. Here, we review the major findings of research of heritable microbial endosymbionts of butterflies and moths. We promote the Lepidoptera as important models in the study of reproductive manipulations employed by heritable endosymbionts, with the mechanisms underlying male-killing and feminisation currently being elucidated in moths and butterflies. We also reveal that the vast majority of research undertaken of Lepidopteran endosymbionts concerns Wolbachia. While this highly prevalent bacterium is undoubtedly important, studies should move towards investigating the presence of other, and interacting endosymbionts, and we discuss the merits of examining the microbiome of Lepidoptera to this end. We finally consider the importance of understanding the influence of endosymbionts under global environmental change and when planning conservation management of endangered Lepidoptera species. PMID:29761037

Improving record linkage performance in the presence of missing linkage data.

PubMed

Ong, Toan C; Mannino, Michael V; Schilling, Lisa M; Kahn, Michael G

2014-12-01

Existing record linkage methods do not handle missing linking field values in an efficient and effective manner. The objective of this study is to investigate three novel methods for improving the accuracy and efficiency of record linkage when record linkage fields have missing values. By extending the Fellegi-Sunter scoring implementations available in the open-source Fine-grained Record Linkage (FRIL) software system we developed three novel methods to solve the missing data problem in record linkage, which we refer to as: Weight Redistribution, Distance Imputation, and Linkage Expansion. Weight Redistribution removes fields with missing data from the set of quasi-identifiers and redistributes the weight from the missing attribute based on relative proportions across the remaining available linkage fields. Distance Imputation imputes the distance between the missing data fields rather than imputing the missing data value. Linkage Expansion adds previously considered non-linkage fields to the linkage field set to compensate for the missing information in a linkage field. We tested the linkage methods using simulated data sets with varying field value corruption rates. The methods developed had sensitivity ranging from .895 to .992 and positive predictive values (PPV) ranging from .865 to 1 in data sets with low corruption rates. Increased corruption rates lead to decreased sensitivity for all methods. These new record linkage algorithms show promise in terms of accuracy and efficiency and may be valuable for combining large data sets at the patient level to support biomedical and clinical research. Copyright © 2014 Elsevier Inc. All rights reserved.

Reporting and dealing with missing quality of life data in RCTs: has the picture changed in the last decade?

PubMed

Fielding, S; Ogbuagu, A; Sivasubramaniam, S; MacLennan, G; Ramsay, C R

2016-12-01

Missing data are a major problem in the analysis of data from randomised trials affecting power and potentially producing biased treatment effects. Specifically focussing on quality of life outcomes, we aimed to report the amount of missing data, whether imputation was used and what methods and was the missing mechanism discussed from four leading medical journals and compare the picture to our previous review nearly a decade ago. A random selection (50 %) of all RCTS published during 2013-2014 in BMJ, JAMA, Lancet and NEJM was obtained. RCTs reported in research letters, cluster RCTs, non-randomised designs, review articles and meta-analysis were excluded. We included 87 RCTs in the review of which 35 % the amount of missing primary QoL data was unclear, 31 (36 %) used imputation. Only 23 % discussed the missing data mechanism. Nearly half used complete case analysis. Reporting was more unclear for secondary QoL outcomes. Compared to the previous review, multiple imputation was used more prominently but mainly in sensitivity analysis. Inadequate reporting and handling of missing QoL data in RCTs are still an issue. There is a large gap between statistical methods research relating to missing data and the use of the methods in applications. A sensitivity analysis should be undertaken to explore the sensitivity of the main results to different missing data assumptions. Medical journals can help to improve the situation by requiring higher standards of reporting and analytical methods to deal with missing data, and by issuing guidance to authors on expected standard.

[Missed lessons, missed opportunities: a role for public health services in medical absenteeism in young people].

PubMed

Vanneste, Y T M; van de Goor, L A M; Feron, F J M

2016-01-01

Young people who often miss school for health reasons are not only missing education, but also the daily routine of school, and social intercourse with their classmates. Medical absenteeism among students merits greater attention. For a number of years, in various regions in the Netherlands, students with extensive medical absenteeism have been invited to see a youth healthcare specialist. The MASS intervention (Medical Advice of Students reported Sick; in Dutch: Medische Advisering van de Ziekgemelde Leerling, abbreviated as M@ZL) has been developed by the West Brabant Regional Public Health Service together with secondary schools to address school absenteeism due to reporting sick. In this paper we discuss the MASS intervention and explain why attention should be paid by public health services to the problem of school absenteeism, especially absenteeism on health grounds.

The executive prominent/memory prominent spectrum in Alzheimer’s disease is highly heritable

PubMed Central

Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy; Fardo, David W.; Trittschuh, Emily; Sutti, Sheila; Sherva, Richard; Kauwe, John S.; Naj, Adam C.; Beecham, Gary W.; Gross, Alden; Saykin, Andrew J.; Green, Robert C.; Crane, Paul K.

2016-01-01

Late-onset Alzheimer’s disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer’s Coordinating Center and the Alzheimer’s Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%–7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself. PMID:27103524

The executive prominent/memory prominent spectrum in Alzheimer's disease is highly heritable.

PubMed

Mez, Jesse; Mukherjee, Shubhabrata; Thornton, Timothy; Fardo, David W; Trittschuh, Emily; Sutti, Sheila; Sherva, Richard; Kauwe, John S; Naj, Adam C; Beecham, Gary W; Gross, Alden; Saykin, Andrew J; Green, Robert C; Crane, Paul K

2016-05-01

Late-onset Alzheimer's disease (LOAD) can present heterogeneously, with several subtypes recognized, including dysexecutive AD. One way to identify people with dysexecutive AD is to consider the difference between memory and executive functioning, which we refer to as the executive prominent/memory prominent spectrum. We aimed to determine if this spectrum was heritable. We used neuropsychological and genetic data from people with mild LOAD (Clinical Dementia Rating 0.5 or 1.0) from the National Alzheimer's Coordinating Center and the Alzheimer's Disease Neuroimaging Initiative. We cocalibrated the neuropsychological data to obtain executive functioning and memory scores and used their difference as a continuous phenotype to calculate its heritability overall and by chromosome. Narrow-sense heritability of the difference between memory and executive functioning scores was 0.68 (standard error 0.12). Single nucleotide polymorphisms on chromosomes 1, 2, 4, 11, 12, and 18 explained the largest fraction of phenotypic variance, with signals from each chromosome accounting for 5%-7%. The chromosomal pattern of heritability differed substantially from that of LOAD itself. Copyright © 2016 Elsevier Inc. All rights reserved.

Pregnancy failure and heritable thrombophilia.

PubMed

Middeldorp, Saskia

2007-04-01

Heritable thrombophilia is associated with an increased risk for pregnancy failure, defined as sporadic and recurrent miscarriage, late fetal loss, and other vascular pregnancy complications such as preeclampsia and intrauterine growth retardation. The pathogenesis is likely to include effects on trophoblast differentiation and not solely hypercoagulability. This is in line with the observation that most recurrent miscarriages occur early. Therapeutic options include aspirin as well as low-molecular-weight heparin. However, in women with heritable thrombophilia and unexplained recurrent pregnancy loss, evidence is not available as published trials have not used an adequate comparator (no treatment or placebo). Currently, randomized controlled trials with no treatment or placebo are being carried out and results should be awaited before implementing a potentially harmful intervention in pregnant women with heritable thrombophilia and a history of pregnancy failure. Both infertility and pregnancy failure are extremely distressing for couples with the desire to have children. Pregnancy failure comprises (recurrent) early miscarriage, as well as late pregnancy loss. The role of heritable thrombophilia in pregnancy failure is reviewed, with a focus on recurrent miscarriage, in terms of epidemiology, etiology, and potential therapeutic implications.

[Near miss outcomes in gambling games].

PubMed

Pecsenye, Zsuzsa; Kurucz, Gyozo

2017-01-01

Games of chance operate with an intermittent reinforcement schedule in which the number of games takes the player to win differ in each turn thus they can not predict when the next positive reinforcement arrives. The near miss outcome (close to winning but actually a losing outcome) can be interpreted as a secondary (built in) reinforcement within variable ratio reinforcement schedule that presumably contribute to the development and maintanance of gambling addiction. The aim of this publication would be to introduce near miss outcomes and to summarize and critically analyze literature connected to this issue.We searched internet datebases using word "near miss" and analyse articles focusing on gambling games. Based on numerous authors' results a near miss rate set at around 30% increases the desire to continue playing among gamblers and players who have no former gambling experience as well. Some studies have demonstrated that this effect might be related to the extent the player has the situation under control during the gambling session. The hypothetical inhibiting effect of a 45% near miss ratio has not yet been proven. Neurobiological researches show middle-cerebral activity during near miss outcomes furthermore similar physiological patterns have been discovered following a near miss and winning outcomes. Regarding the connection between intrapsychic variables (cognitive and personality factors) and near misses there are very few studies. The fact that different authors interpret near miss outcomes differently even when studying the same game leads to problems in interpreting their results. It follows from the foregoing empirical results that near miss outcomes contribute to the development and maintanance of pathological gambling but we have little information on the factors implementing this effect.

Paternal ADHD Symptoms and Child Conduct Problems: Is Father Involvement Always Beneficial?

PubMed Central

Romirowsky, Abigail Mintz; Chronis-Tuscano, Andrea

2013-01-01

Background Maternal psychopathology robustly predicts poor developmental and treatment outcomes for children with attention-deficit/hyperactivity disorder (ADHD). Despite the high heritability of ADHD, few studies have examined associations between paternal ADHD symptoms and child adjustment, and none have also considered degree of paternal involvement in childrearing. Identification of modifiable risk factors for child conduct problems is particularly important in this population given the serious adverse outcomes resulting from this comorbidity. Methods This cross-sectional study examined the extent to which paternal involvement in childrearing moderated the association between paternal ADHD symptoms and child conduct problems among 37 children with ADHD and their biological fathers. Results Neither paternal ADHD symptoms nor involvement was independently associated with child conduct problems. However, the interaction between paternal ADHD symptoms and involvement was significant, such that paternal ADHD symptoms were positively associated with child conduct problems only when fathers were highly involved in childrearing. Conclusions The presence of adult ADHD symptoms may determine whether father involvement in childrearing has a positive or detrimental influence on comorbid child conduct problems. PMID:25250402

Missing persons-missing data: the need to collect antemortem dental records of missing persons.

PubMed

Blau, Soren; Hill, Anthony; Briggs, Christopher A; Cordner, Stephen M

2006-03-01

The subject of missing persons is of great concern to the community with numerous associated emotional, financial, and health costs. This paper examines the forensic medical issues raised by the delayed identification of individuals classified as "missing" and highlights the importance of including dental data in the investigation of missing persons. Focusing on Australia, the current approaches employed in missing persons investigations are outlined. Of particular significance is the fact that each of the eight Australian states and territories has its own Missing Persons Unit that operates within distinct state and territory legislation. Consequently, there is a lack of uniformity within Australia about the legal and procedural framework within which investigations of missing persons are conducted, and the interaction of that framework with coronial law procedures. One of the main investigative problems in missing persons investigations is the lack of forensic medical, particularly, odontological input. Forensic odontology has been employed in numerous cases in Australia where identity is unknown or uncertain because of remains being skeletonized, incinerated, or partly burnt. The routine employment of the forensic odontologist to assist in missing person inquiries, has however, been ignored. The failure to routinely employ forensic odontology in missing persons inquiries has resulted in numerous delays in identification. Three Australian cases are presented where the investigation of individuals whose identity was uncertain or unknown was prolonged due to the failure to utilize the appropriate (and available) dental resources. In light of the outcomes of these cases, we suggest that a national missing persons dental records database be established for future missing persons investigations. Such a database could be easily managed between a coronial system and a forensic medical institute. In Australia, a national missing persons dental records database could be incorporated into the National Coroners Information System (NCIS) managed, on behalf of Australia's Coroners, by the Victorian Institute of Forensic Medicine. The existence of the NCIS would ensure operational collaboration in the implementation of the system and cost savings to Australian policing agencies involved in missing person inquiries. The implementation of such a database would facilitate timely and efficient reconciliation of clinical and postmortem dental records and have subsequent social and financial benefits.

Higher heritabilities for gait components than for overall gait scores may improve mobility in ducks.

PubMed

Duggan, Brendan M; Rae, Anne M; Clements, Dylan N; Hocking, Paul M

2017-05-02

Genetic progress in selection for greater body mass and meat yield in poultry has been associated with an increase in gait problems which are detrimental to productivity and welfare. The incidence of suboptimal gait in breeding flocks is controlled through the use of a visual gait score, which is a subjective assessment of walking ability of each bird. The subjective nature of the visual gait score has led to concerns over its effectiveness in reducing the incidence of suboptimal gait in poultry through breeding. The aims of this study were to assess the reliability of the current visual gait scoring system in ducks and to develop a more objective method to select for better gait. Experienced gait scorers assessed short video clips of walking ducks to estimate the reliability of the current visual gait scoring system. Kendall's coefficients of concordance between and within observers were estimated at 0.49 and 0.75, respectively. In order to develop a more objective scoring system, gait components were visually scored on more than 4000 pedigreed Pekin ducks and genetic parameters were estimated for these components. Gait components, which are a more objective measure, had heritabilities that were as good as, or better than, those of the overall visual gait score. Measurement of gait components is simpler and therefore more objective than the standard visual gait score. The recording of gait components can potentially be automated, which may increase accuracy further and may improve heritability estimates. Genetic correlations were generally low, which suggests that it is possible to use gait components to select for an overall improvement in both economic traits and gait as part of a balanced breeding programme.

Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review

PubMed Central

Mercieca-Bebber, Rebecca; Palmer, Michael J; Brundage, Michael; Stockler, Martin R; King, Madeleine T

2016-01-01

Objectives Patient-reported outcomes (PROs) provide important information about the impact of treatment from the patients' perspective. However, missing PRO data may compromise the interpretability and value of the findings. We aimed to report: (1) a non-technical summary of problems caused by missing PRO data; and (2) a systematic review by collating strategies to: (A) minimise rates of missing PRO data, and (B) facilitate transparent interpretation and reporting of missing PRO data in clinical research. Our systematic review does not address statistical handling of missing PRO data. Data sources MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases (inception to 31 March 2015), and citing articles and reference lists from relevant sources. Eligibility criteria English articles providing recommendations for reducing missing PRO data rates, or strategies to facilitate transparent interpretation and reporting of missing PRO data were included. Methods 2 reviewers independently screened articles against eligibility criteria. Discrepancies were resolved with the research team. Recommendations were extracted and coded according to framework synthesis. Results 117 sources (55% discussion papers, 26% original research) met the eligibility criteria. Design and methodological strategies for reducing rates of missing PRO data included: incorporating PRO-specific information into the protocol; carefully designing PRO assessment schedules and defining termination rules; minimising patient burden; appointing a PRO coordinator; PRO-specific training for staff; ensuring PRO studies are adequately resourced; and continuous quality assurance. Strategies for transparent interpretation and reporting of missing PRO data include utilising auxiliary data to inform analysis; transparently reporting baseline PRO scores, rates and reasons for missing data; and methods for handling missing PRO data. Conclusions The instance of missing PRO data and its potential to bias clinical research can be minimised by implementing thoughtful design, rigorous methodology and transparent reporting strategies. All members of the research team have a responsibility in implementing such strategies. PMID:27311907

Genome-wide epigenetic perturbation jump-starts patterns of heritable variation found in nature.

PubMed

Roux, Fabrice; Colomé-Tatché, Maria; Edelist, Cécile; Wardenaar, René; Guerche, Philippe; Hospital, Frédéric; Colot, Vincent; Jansen, Ritsert C; Johannes, Frank

2011-08-01

We extensively phenotyped 6000 Arabidopsis plants with experimentally perturbed DNA methylomes as well as a diverse panel of natural accessions in a common garden. We found that alterations in DNA methylation not only caused heritable phenotypic diversity but also produced heritability patterns closely resembling those of the natural accessions. Our findings indicate that epigenetically induced and naturally occurring variation in complex traits share part of their polygenic architecture and may offer complementary adaptation routes in ecological settings.

Pearls and pitfalls in genetic studies of migraine.

PubMed

Eising, Else; de Vries, Boukje; Ferrari, Michel D; Terwindt, Gisela M; van den Maagdenberg, Arn M J M

2013-06-01

Migraine is a prevalent neurovascular brain disorder with a strong genetic component, and different methodological approaches have been implemented to identify the genes involved. This review focuses on pearls and pitfalls of these approaches and genetic findings in migraine. Common forms of migraine (i.e. migraine with and without aura) are thought to have a polygenic make-up, whereas rare familial hemiplegic migraine (FHM) presents with a monogenic pattern of inheritance. Until a few years ago only studies in FHM yielded causal genes, which were identified by a classical linkage analysis approach. Functional analyses of FHM gene mutations in cellular and transgenic animal models suggest abnormal glutamatergic neurotransmission as a possible key disease mechanism. Recently, a number of genes were discovered for the common forms of migraine using a genome-wide association (GWA) approach, which sheds first light on the pathophysiological mechanisms involved. Novel technological strategies such as next-generation sequencing, which can be implemented in future genetic migraine research, may aid the identification of novel FHM genes and promote the search for the missing heritability of common migraine.

Modeling and Analysis of Wholesale Electricity Market Design. Understanding the Missing Money Problem. December 2013 - January 2015

DOE Office of Scientific and Technical Information (OSTI.GOV)

Papalexopoulos, A.; Hansen, C.; Perrino, D.

This project examined the impact of renewable energy sources, which have zero incremental energy costs, on the sustainability of conventional generation. This “missing money” problem refers to market outcomes in which infra-marginal energy revenues in excess of operations and maintenance (O&M) costs are systematically lower than the amortized costs of new entry for a marginal generator. The problem is caused by two related factors: (1) conventional generation is dispatched less, and (2) the price that conventional generation receives for its energy is lower. This lower revenue stream may not be sufficient to cover both the variable and fixed costs ofmore » conventional generation. In fact, this study showed that higher wind penetrations in the Electric Reliability Council of Texas (ERCOT) system could cause many conventional generators to become uneconomic.« less

A method to estimate the additional uncertainty in gap-filled NEE resulting from long gaps in the CO2 flux record

Treesearch

Andrew D. Richardson; David Y. Hollinger

2007-01-01

Missing values in any data set create problems for researchers. The process by which missing values are replaced, and the data set is made complete, is generally referred to as imputation. Within the eddy flux community, the term "gap filling" is more commonly applied. A major challenge is that random errors in measured data result in uncertainty in the gap-...

Heritability of hoarding symptoms across adolescence and young adulthood: A longitudinal twin study.

PubMed

Ivanov, Volen Z; Nordsletten, Ashley; Mataix-Cols, David; Serlachius, Eva; Lichtenstein, Paul; Lundström, Sebastian; Magnusson, Patrik K E; Kuja-Halkola, Ralf; Rück, Christian

2017-01-01

Twin studies of hoarding symptoms indicate low to moderate heritability during adolescence and considerably higher heritability in older samples, suggesting dynamic developmental etiological effects. The aim of the current study was to estimate the relative contribution of additive genetic and environmental effects to hoarding symptoms during adolescence and young adulthood and to estimate the sources of stability and change of hoarding symptoms during adolescence. Univariate model-fitting was conducted in three cohorts of twins aged 15 (n = 7,905), 18 (n = 2,495) and 20-28 (n = 6,218). Longitudinal analyses were conducted in a subsample of twins for which data on hoarding symptoms was available at both age 15 and 18 (n = 1,701). Heritability estimates for hoarding symptoms at ages 15, 18 and 20-28 were 41% (95% confidence interval [CI]: 36-45%), 31% (95% CI: 22-39%) and 29% (95% CI: 24-34%) respectively. Quantitative sex-differences emerged in twins aged 15 at which point the heritability in boys was 33% (95% CI: 22-41%) and 17% (95% CI: 0-36%) in girls. Shared environmental effects played a negligible role across all samples with the exception of girls aged 15 where they accounted for a significant proportion of the variance (22%; 95% CI 6-36%). The longitudinal bivariate analyses revealed a significant phenotypic correlation of hoarding symptoms between ages 15 and 18 (0.40; 95% CI: 0.36-0.44) and a strong but imperfect genetic correlation (0.75; 95% CI: 0.57-0.94). The bivariate heritability was estimated to 65% (95% CI: 50-79%). Hoarding symptoms are heritable from adolescence throughout young adulthood, although heritability appears to slightly decrease over time. Shared environmental effects contribute to hoarding symptoms only in girls at age 15. The stability of hoarding symptoms between ages 15 and 18 is largely explained by genetic factors, while non-shared environmental factors primarily have a time-specific effect. The findings indicate that dynamic developmental etiological effects may be operating across the life span.

Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis

PubMed Central

Zhou, Kaixin; Donnelly, Louise; Yang, Jian; Li, Miaoxin; Deshmukh, Harshal; Van Zuydam, Natalie; Ahlqvist, Emma; Spencer, Chris C; Groop, Leif; Morris, Andrew D; Colhoun, Helen M; Sham, Pak C; McCarthy, Mark I; Palmer, Colin N A; Pearson, Ewan R

2014-01-01

Summary Background Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. Methods In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. Findings 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1–68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Interpretation Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action. Funding Wellcome Trust. PMID:24731673

Heritability of the Severity of the Metabolic Syndrome in Whites and Blacks in 3 Large Cohorts.

PubMed

Musani, Solomon K; Martin, Lisa J; Woo, Jessica G; Olivier, Michael; Gurka, Matthew J; DeBoer, Mark D

2017-04-01

Although dichotomous criteria for the metabolic syndrome (MetS) appear heritable, it is not known whether MetS severity as assessed by a continuous MetS score is heritable and whether this varies by race. We used SOLAR (Sequential Oligogenic Linkage Analysis Routines) to evaluate heritability of Adult Treatment Panel-III MetS and a sex- and race-specific MetS severity Z score among 3 large familial cohorts: the JHS (Jackson Heart Study, 1404 black participants), TOPS (Take Off Pounds Sensibly, 1947 white participants), and PLRS (Princeton Lipid Research Study, 229 black and 527 white participants). Heritability estimates were larger for Adult Treatment Panel-III MetS among black compared with white cohort members (JHS 0.48; 95% confidence interval [CI], 0.28-0.68 and PLRS blacks 0.93 [95% CI, 0.73-1.13] versus TOPS 0.21 [95% CI, -0.18 to 0.60] and PLRS whites 0.27 [95% CI, -0.04 to 0.58]). The difference by race narrowed when assessing heritability of the MetS severity score (JHS 0.52 [95% CI, 0.38, 0.66] and PLRS blacks 0.64 [95% CI, 0.13-1.15] versus TOPS 0.23 [95% CI, 0.15-0.31] and PLRS whites 0.60 [95% CI, 0.33-0.87]). There was a high degree of genetic and phenotypic correlation between MetS severity and the individual components of MetS among all groups, although the genetic correlations failed to reach statistical significance among PLRS blacks. Meta-analyses revealed a combined heritability estimate for Adult Treatment Panel-III MetS of 0.24 (95% CI, 0.11-0.36) and for the MetS severity score of 0.50 (95% CI, -0.05 to 0.99). MetS severity seems highly heritable among whites and blacks. This continuous MetS severity Z score may provide a more useful means of characterizing phenotypic MetS in genetic studies by minimizing racial differences. © 2017 American Heart Association, Inc.

Prevalence, associated factors and heritabilities of metabolic syndrome and its individual components in African Americans: the Jackson Heart Study.

PubMed

Khan, Rumana J; Gebreab, Samson Y; Sims, Mario; Riestra, Pia; Xu, Ruihua; Davis, Sharon K

2015-11-01

Both environmental and genetic factors play important roles in the development of metabolic syndrome (MetS). Studies about its associated factors and genetic contribution in African Americans (AA) are sparse. Our aim was to report the prevalence, associated factors and heritability estimates of MetS and its components in AA men and women. Data of this cross-sectional study come from a large community-based Jackson Heart Study (JHS). We analysed a total of 5227 participants, of whom 1636 from 281 families were part of a family study subset of JHS. Participants were classified as having MetS according to the Adult Treatment Panel III criteria. Multiple logistic regression analysis was performed to isolate independently associated factors of MetS (n=5227). Heritability was estimated from the family study subset using variance component methods (n=1636). About 27% of men and 40% of women had MetS. For men, associated factors with having MetS were older age, lower physical activity, higher body mass index, and higher homocysteine and adiponectin levels (p<0.05 for all). For women, in addition to all these, lower education, current smoking and higher stress were also significant (p<0.05 for all). After adjusting for covariates, the heritability of MetS was 32% (p<0.001). Heritability ranged from 14 to 45% among its individual components. Relatively higher heritability was estimated for waist circumference (45%), high density lipoprotein-cholesterol (43%) and triglycerides (42%). Heritability of systolic blood pressure (BP), diastolic BP and fasting blood glucose was 16%, 15% and 14%, respectively. Stress and low education were associated with having MetS in AA women, but not in men. Higher heritability estimates for lipids and waist circumference support the hypothesis of lipid metabolism playing a central role in the development of MetS and encourage additional efforts to identify the underlying susceptibility genes for this syndrome in AA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.

PubMed

Zhou, Kaixin; Donnelly, Louise; Yang, Jian; Li, Miaoxin; Deshmukh, Harshal; Van Zuydam, Natalie; Ahlqvist, Emma; Spencer, Chris C; Groop, Leif; Morris, Andrew D; Colhoun, Helen M; Sham, Pak C; McCarthy, Mark I; Palmer, Colin N A; Pearson, Ewan R

2014-06-01

Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0·022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action. Wellcome Trust. Copyright © 2014 Elsevier Ltd. All rights reserved.

A review of the handling of missing longitudinal outcome data in clinical trials

PubMed Central

2014-01-01

The aim of this review was to establish the frequency with which trials take into account missingness, and to discover what methods trialists use for adjustment in randomised controlled trials with longitudinal measurements. Failing to address the problems that can arise from missing outcome data can result in misleading conclusions. Missing data should be addressed as a means of a sensitivity analysis of the complete case analysis results. One hundred publications of randomised controlled trials with longitudinal measurements were selected randomly from trial publications from the years 2005 to 2012. Information was extracted from these trials, including whether reasons for dropout were reported, what methods were used for handing the missing data, whether there was any explanation of the methods for missing data handling, and whether a statistician was involved in the analysis. The main focus of the review was on missing data post dropout rather than missing interim data. Of all the papers in the study, 9 (9%) had no missing data. More than half of the papers included in the study failed to make any attempt to explain the reasons for their choice of missing data handling method. Of the papers with clear missing data handling methods, 44 papers (50%) used adequate methods of missing data handling, whereas 30 (34%) of the papers used missing data methods which may not have been appropriate. In the remaining 17 papers (19%), it was difficult to assess the validity of the methods used. An imputation method was used in 18 papers (20%). Multiple imputation methods were introduced in 1987 and are an efficient way of accounting for missing data in general, and yet only 4 papers used these methods. Out of the 18 papers which used imputation, only 7 displayed the results as a sensitivity analysis of the complete case analysis results. 61% of the papers that used an imputation explained the reasons for their chosen method. Just under a third of the papers made no reference to reasons for missing outcome data. There was little consistency in reporting of missing data within longitudinal trials. PMID:24947664

Mining Missing Hyperlinks from Human Navigation Traces: A Case Study of Wikipedia.

PubMed

West, Robert; Paranjape, Ashwin; Leskovec, Jure

Hyperlinks are an essential feature of the World Wide Web. They are especially important for online encyclopedias such as Wikipedia: an article can often only be understood in the context of related articles, and hyperlinks make it easy to explore this context. But important links are often missing, and several methods have been proposed to alleviate this problem by learning a linking model based on the structure of the existing links. Here we propose a novel approach to identifying missing links in Wikipedia. We build on the fact that the ultimate purpose of Wikipedia links is to aid navigation. Rather than merely suggesting new links that are in tune with the structure of existing links, our method finds missing links that would immediately enhance Wikipedia's navigability. We leverage data sets of navigation paths collected through a Wikipedia-based human-computation game in which users must find a short path from a start to a target article by only clicking links encountered along the way. We harness human navigational traces to identify a set of candidates for missing links and then rank these candidates. Experiments show that our procedure identifies missing links of high quality.

Exemplar-based inpainting as a solution to the missing wedge problem in electron tomography.

PubMed

Trampert, Patrick; Wang, Wu; Chen, Delei; Ravelli, Raimond B G; Dahmen, Tim; Peters, Peter J; Kübel, Christian; Slusallek, Philipp

2018-04-21

A new method for dealing with incomplete projection sets in electron tomography is proposed. The approach is inspired by exemplar-based inpainting techniques in image processing and heuristically generates data for missing projection directions. The method has been extended to work on three dimensional data. In general, electron tomography reconstructions suffer from elongation artifacts along the beam direction. These artifacts can be seen in the corresponding Fourier domain as a missing wedge. The new method synthetically generates projections for these missing directions with the help of a dictionary based approach that is able to convey both structure and texture at the same time. It constitutes a preprocessing step that can be combined with any tomographic reconstruction algorithm. The new algorithm was applied to phantom data, to a real electron tomography data set taken from a catalyst, as well as to a real dataset containing solely colloidal gold particles. Visually, the synthetic projections, reconstructions, and corresponding Fourier power spectra showed a decrease of the typical missing wedge artifacts. Quantitatively, the inpainting method is capable to reduce missing wedge artifacts and improves tomogram quality with respect to full width half maximum measurements. Copyright © 2018. Published by Elsevier B.V.

Mining Missing Hyperlinks from Human Navigation Traces: A Case Study of Wikipedia

PubMed Central

West, Robert; Paranjape, Ashwin; Leskovec, Jure

2015-01-01

Hyperlinks are an essential feature of the World Wide Web. They are especially important for online encyclopedias such as Wikipedia: an article can often only be understood in the context of related articles, and hyperlinks make it easy to explore this context. But important links are often missing, and several methods have been proposed to alleviate this problem by learning a linking model based on the structure of the existing links. Here we propose a novel approach to identifying missing links in Wikipedia. We build on the fact that the ultimate purpose of Wikipedia links is to aid navigation. Rather than merely suggesting new links that are in tune with the structure of existing links, our method finds missing links that would immediately enhance Wikipedia's navigability. We leverage data sets of navigation paths collected through a Wikipedia-based human-computation game in which users must find a short path from a start to a target article by only clicking links encountered along the way. We harness human navigational traces to identify a set of candidates for missing links and then rank these candidates. Experiments show that our procedure identifies missing links of high quality. PMID:26634229

[The genetics of collagen diseases].

PubMed

Kaplan, J; Maroteaux, P; Frezal, J

1986-01-01

Heritable disorders of collagen include Ehler-Danlos syndromes (11 types are actually known), Larsen syndrome and osteogenesis imperfecta. Their clinical, genetic and biochemical features are reviewed. Marfan syndrome is closely related to heritable disorders of collagen.

Heritability of tic disorders: a twin-family study.

PubMed

Zilhão, N R; Olthof, M C; Smit, D J A; Cath, D C; Ligthart, L; Mathews, C A; Delucchi, K; Boomsma, D I; Dolan, C V

2017-04-01

Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. In an extended twin-family design, we analysed lifetime tic data reported by adult mono- and dizygotic twins (n = 8323) and their family members (n = 7164; parents and siblings) from 7311 families in the Netherlands Twin Register. We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes. Heritability was estimated by genetic structural equation modeling for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between 0.25 and 0.37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment or non-additive genetic effects. Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSM-IV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies.

Heritability and phenotypic variation of canine hip dysplasia radiographic traits in a cohort of Australian German shepherd dogs.

PubMed

Wilson, Bethany J; Nicholas, Frank W; James, John W; Wade, Claire M; Tammen, Imke; Raadsma, Herman W; Castle, Kao; Thomson, Peter C

2012-01-01

Canine Hip Dysplasia (CHD) is a common, painful and debilitating orthopaedic disorder of dogs with a partly genetic, multifactorial aetiology. Worldwide, potential breeding dogs are evaluated for CHD using radiographically based screening schemes such as the nine ordinally-scored British Veterinary Association Hip Traits (BVAHTs). The effectiveness of selective breeding based on screening results requires that a significant proportion of the phenotypic variation is caused by the presence of favourable alleles segregating in the population. This proportion, heritability, was measured in a cohort of 13,124 Australian German Shepherd Dogs born between 1976 and 2005, displaying phenotypic variation for BVAHTs, using ordinal, linear and binary mixed models fitted by a Restricted Maximum Likelihood method. Heritability estimates for the nine BVAHTs ranged from 0.14-0.24 (ordinal models), 0.14-0.25 (linear models) and 0.12-0.40 (binary models). Heritability for the summed BVAHT phenotype was 0.30 ± 0.02. The presence of heritable variation demonstrates that selection based on BVAHTs has the potential to improve BVAHT scores in the population. Assuming a genetic correlation between BVAHT scores and CHD-related pain and dysfunction, the welfare of Australian German Shepherds can be improved by continuing to consider BVAHT scores in the selection of breeding dogs, but that as heritability values are only moderate in magnitude the accuracy, and effectiveness, of selection could be improved by the use of Estimated Breeding Values in preference to solely phenotype based selection of breeding animals.

Estimating the potential for adaptation of corals to climate warming.

PubMed

Császár, Nikolaus B M; Ralph, Peter J; Frankham, Richard; Berkelmans, Ray; van Oppen, Madeleine J H

2010-03-18

The persistence of tropical coral reefs is threatened by rapidly increasing climate warming, causing a functional breakdown of the obligate symbiosis between corals and their algal photosymbionts (Symbiodinium) through a process known as coral bleaching. Yet the potential of the coral-algal symbiosis to genetically adapt in an evolutionary sense to warming oceans is unknown. Using a quantitative genetics approach, we estimated the proportion of the variance in thermal tolerance traits that has a genetic basis (i.e. heritability) as a proxy for their adaptive potential in the widespread Indo-Pacific reef-building coral Acropora millepora. We chose two physiologically different populations that associate respectively with one thermo-tolerant (Symbiodinium clade D) and one less tolerant symbiont type (Symbiodinium C2). In both symbiont types, pulse amplitude modulated (PAM) fluorometry and high performance liquid chromatography (HPLC) analysis revealed significant heritabilities for traits related to both photosynthesis and photoprotective pigment profile. However, quantitative real-time polymerase chain reaction (qRT-PCR) assays showed a lack of heritability in both coral host populations for their own expression of fundamental stress genes. Coral colony growth, contributed to by both symbiotic partners, displayed heritability. High heritabilities for functional key traits of algal symbionts, along with their short clonal generation time and high population sizes allow for their rapid thermal adaptation. However, the low overall heritability of coral host traits, along with the corals' long generation time, raise concern about the timely adaptation of the coral-algal symbiosis in the face of continued rapid climate warming.

Risk of herbivore attack and heritability of ontogenetic trajectories in plant defense.

PubMed

Ochoa-López, Sofía; Rebollo, Roberto; Barton, Kasey E; Fornoni, Juan; Boege, Karina

2018-06-01

Ontogeny has been identified as a main source of variation in the expression of plant phenotypes. However, there is limited information on the mechanisms behind the evolution of ontogenetic trajectories in plant defense. We explored if risk of attack, herbivore damage, heritability, and phenotypic plasticity can promote or constrain the evolutionary potential of ontogenetic trajectories in three defensive traits. We exposed 20 genotypes of Turnera velutina to contrasting environments (shadehouse and field plots), and measured the cyanogenic potential, trichome density, and sugar content in extrafloral nectar in seedlings, juveniles and reproductive plants. We also assessed risk of attack through oviposition preferences, and quantified herbivore damage in the field. We estimated genetic variance, broad sense heritability, and evolvability of the defensive traits at each ontogenetic stage, and of the ontogenetic trajectories themselves. For plants growing in the shadehouse, we found genetic variation and broad sense heritability for cyanogenic potential in seedlings, and for trichome density at all ontogenetic stages. Genetic variation and heritability of ontogenetic trajectories was detected for trichome density only. These genetic pre-requisites for evolution, however, were not detected in the field, suggesting that environmental variation and phenotypic plastic responses mask any heritable variation. Finally, ontogenetic trajectories were found to be plastic, differing between shadehouse and field conditions for the same genetic families. Overall, we provide support for the idea that changes in herbivore pressure can be a mechanism behind the evolution of ontogenetic trajectories. This evolutionary potential, however, can be constrained by phenotypic plasticity expressed in heterogeneous environments.

Estimating the Potential for Adaptation of Corals to Climate Warming

PubMed Central

Császár, Nikolaus B. M.; Ralph, Peter J.; Frankham, Richard; Berkelmans, Ray; van Oppen, Madeleine J. H.

2010-01-01

The persistence of tropical coral reefs is threatened by rapidly increasing climate warming, causing a functional breakdown of the obligate symbiosis between corals and their algal photosymbionts (Symbiodinium) through a process known as coral bleaching. Yet the potential of the coral-algal symbiosis to genetically adapt in an evolutionary sense to warming oceans is unknown. Using a quantitative genetics approach, we estimated the proportion of the variance in thermal tolerance traits that has a genetic basis (i.e. heritability) as a proxy for their adaptive potential in the widespread Indo-Pacific reef-building coral Acropora millepora. We chose two physiologically different populations that associate respectively with one thermo-tolerant (Symbiodinium clade D) and one less tolerant symbiont type (Symbiodinium C2). In both symbiont types, pulse amplitude modulated (PAM) fluorometry and high performance liquid chromatography (HPLC) analysis revealed significant heritabilities for traits related to both photosynthesis and photoprotective pigment profile. However, quantitative real-time polymerase chain reaction (qRT-PCR) assays showed a lack of heritability in both coral host populations for their own expression of fundamental stress genes. Coral colony growth, contributed to by both symbiotic partners, displayed heritability. High heritabilities for functional key traits of algal symbionts, along with their short clonal generation time and high population sizes allow for their rapid thermal adaptation. However, the low overall heritability of coral host traits, along with the corals' long generation time, raise concern about the timely adaptation of the coral-algal symbiosis in the face of continued rapid climate warming. PMID:20305781

Nature vs nurture: are leaders born or made? A behavior genetic investigation of leadership style.

PubMed

Johnson, A M; Vernon, P A; McCarthy, J M; Molson, M; Harris, J A; Jang, K L

1998-12-01

With the recent resurgence in popularity of trait theories of leadership, it is timely to consider the genetic determination of the multiple factors comprising the leadership construct. Individual differences in personality traits have been found to be moderately to highly heritable, and so it follows that if there are reliable personality trait differences between leaders and non-leaders, then there may be a heritable component to these individual differences. Despite this connection between leadership and personality traits, however, there are no studies of the genetic basis of leadership using modern behavior genetic methodology. The present study proposes to address the lack of research in this area by examining the heritability of leadership style, as measured by self-report psychometric inventories. The Multifactor Leadership Questionnaire (MLQ), the Leadership Ability Evaluation, and the Adjective Checklist were completed by 247 adult twin pairs (183 monozygotic and 64 same-sex dizygotic). Results indicated that most of the leadership dimensions examined in this study are heritable, as are two higher level factors (resembling transactional and transformational leadership) derived from an obliquely rotated principal components factors analysis of the MLQ. Univariate analyses suggested that 48% of the variance in transactional leadership may be explained by additive heritability, and 59% of the variance in transformational leadership may be explained by non-additive (dominance) heritability. Multivariate analyses indicated that most of the variables studied shared substantial genetic covariance, suggesting a large overlap in the underlying genes responsible for the leadership dimensions.

Genetic influences on free and cued recall in long-term memory tasks.

PubMed

Volk, Heather E; McDermott, Kathleen B; Roediger, Henry L; Todd, Richard D

2006-10-01

Long-term memory (LTM) problems are associated with many psychiatric and neurological illnesses and are commonly measured using free and cued recall tasks. Although LTM has been linked with biologic mechanisms, the etiology of distinct LTM tasks is unknown. We studied LTM in 95 healthy female twin pairs identified through birth records in the state of Missouri. Performance on tasks of free recall of unrelated words, free and cued recall of categorized words, and the vocabulary section of the Wechsler Adult Intelligence Scale (WAIS-R) were examined using structural equation modeling. Additive genetic and unique environmental factors influenced LTM and intelligence. Free recall of unrelated and categorized words, and cued recall of categorized words, were moderately heritable (55%, 38%, and 37%). WAIS-R vocabulary score was highly heritable (77%). Controlling for verbal intelligence in multivariate analyses of recall, two components of genetic influence on LTM were found; one for all three recall scores and one for free and cued categorized word recall. Recall of unrelated and categorized words is influenced by different genetic and environmental factors indicating heterogeneity in LTM. Verbal intelligence is etiologically different from LTM indicating that these two abilities utilize different brain functions.

Two quantitative trait loci influence whipworm (Trichuris trichiura) infection in a Nepalese population.

PubMed

Williams-Blangero, Sarah; Vandeberg, John L; Subedi, Janardan; Jha, Bharat; Dyer, Tom D; Blangero, John

2008-04-15

Whipworm (Trichuris trichiura) infection is a soil-transmitted helminth infection that affects >1 billion people. It is a serious public health problem in many developing countries and can result in deficits in growth and cognitive development. In a follow-up study of significant heritability for whipworm infection, we conducted the first genome scan for quantitative trait loci (QTL) influencing the heritability of susceptibility to this important parasitic disease. Whipworm egg counts were determined for 1,253 members of the Jirel population of eastern Nepal. All individuals in the study sample belonged to a single pedigree including >26,000 pairs of relatives that are informative for genetic analysis. Linkage analysis of genome scan data generated for the pedigree provided unambiguous evidence for 2 QTL influencing susceptibility to whipworm infection, one located on chromosome 9 (logarithm of the odds ratio [LOD] score, 3.35; genomewide P = .0138) and the other located on chromosome 18 (LOD score, 3.29; genomewide P = .0159). There was also suggestive evidence that 2 loci located on chromosomes 12 and 13 influenced whipworm infection. The results of this first genome scan for T. trichiura egg counts provides new information on the determinants of genetic predisposition to whipworm infection.

The mean-square error optimal linear discriminant function and its application to incomplete data vectors

NASA Technical Reports Server (NTRS)

Walker, H. F.

1979-01-01

In many pattern recognition problems, data vectors are classified although one or more of the data vector elements are missing. This problem occurs in remote sensing when the ground is obscured by clouds. Optimal linear discrimination procedures for classifying imcomplete data vectors are discussed.

Minimax Rate-optimal Estimation of High-dimensional Covariance Matrices with Incomplete Data*

PubMed Central

Cai, T. Tony; Zhang, Anru

2016-01-01

Missing data occur frequently in a wide range of applications. In this paper, we consider estimation of high-dimensional covariance matrices in the presence of missing observations under a general missing completely at random model in the sense that the missingness is not dependent on the values of the data. Based on incomplete data, estimators for bandable and sparse covariance matrices are proposed and their theoretical and numerical properties are investigated. Minimax rates of convergence are established under the spectral norm loss and the proposed estimators are shown to be rate-optimal under mild regularity conditions. Simulation studies demonstrate that the estimators perform well numerically. The methods are also illustrated through an application to data from four ovarian cancer studies. The key technical tools developed in this paper are of independent interest and potentially useful for a range of related problems in high-dimensional statistical inference with missing data. PMID:27777471

Minimax Rate-optimal Estimation of High-dimensional Covariance Matrices with Incomplete Data.

PubMed

Cai, T Tony; Zhang, Anru

2016-09-01

Missing data occur frequently in a wide range of applications. In this paper, we consider estimation of high-dimensional covariance matrices in the presence of missing observations under a general missing completely at random model in the sense that the missingness is not dependent on the values of the data. Based on incomplete data, estimators for bandable and sparse covariance matrices are proposed and their theoretical and numerical properties are investigated. Minimax rates of convergence are established under the spectral norm loss and the proposed estimators are shown to be rate-optimal under mild regularity conditions. Simulation studies demonstrate that the estimators perform well numerically. The methods are also illustrated through an application to data from four ovarian cancer studies. The key technical tools developed in this paper are of independent interest and potentially useful for a range of related problems in high-dimensional statistical inference with missing data.

Getting patients in the door: medical appointment reminder preferences.

PubMed

Crutchfield, Trisha M; Kistler, Christine E

2017-01-01

Between 23% and 34% of outpatient appointments are missed annually. Patients who frequently miss medical appointments have poorer health outcomes and are less likely to use preventive health care services. Missed appointments result in unnecessary costs and organizational inefficiencies. Appointment reminders may help reduce missed appointments; particular types may be more effective than other types. We used a survey with a discrete choice experiment (DCE) to learn why individuals miss appointments and to assess appointment reminder preferences. We enrolled a national sample of adults from an online survey panel to complete demographic and appointment habit questions as well as a 16-task DCE designed in Sawtooth Software's Discover tool. We assessed preferences for four reminder attributes - initial reminder type, arrival of initial reminder, reminder content, and number of reminders. We derived utilities and importance scores. We surveyed 251 adults nationally, with a mean age of 43 (range 18-83) years: 51% female, 84% White, and 8% African American. Twenty-three percent of individuals missed one or more appointments in the past 12 months. Two primary reasons given for missing an appointment include transportation problems (28%) and forgetfulness (26%). Participants indicated the initial reminder type (21%) was the most important attribute, followed by the number of reminders (10%). Overall, individuals indicated a preference for a single reminder, arriving via email, phone call, or text message, delivered less than 2 weeks prior to an appointment. Preferences for reminder content were less clear. The number of missed appointments and reasons for missing appointments are consistent with prior research. Patient-centered appointment reminders may improve appointment attendance by addressing some of the reasons individuals report missing appointments and by meeting patients' needs. Future research is necessary to determine if preferred reminders used in practice will result in improved appointment attendance in clinical settings.

Informatively missing quality of life and unmet needs sex data for immigrant and Anglo-Australian cancer patients and survivors.

PubMed

Bell, Melanie L; Butow, Phyllis N; Goldstein, David

2013-12-01

Although cancer can seriously affect peoples' sexual well-being, survivors and patients may be reluctant to answer questions about sex. This reluctance may be stronger for immigrants. This study aimed to investigate missing sex data rates and predictors of missingness in two large studies on immigrants and Anglo-Australian controls with cancer and to investigate whether those with missing sex data may have worse sexual outcomes than those with complete data. We carried out two studies aimed at describing the quality of life (QoL) and unmet needs amongst Arabic, Chinese and Greek immigrants versus Anglo-Australians cancer survivors (n = 596, recruited from cancer registries) and patients (n = 845). Logistic regression was used to model the probability of having missing sex data in either of the questionnaires. We compared the mean of the unmet sex needs responses of those who had missing QoL sex data (but not needs) to those who had completed both, and vice versa. Missing sex data rates were as high as 65 %, with immigrants more likely to skip sex items than Anglo-Australians (p = 0.02 for registry study, p < 0.0001 for hospital study). Women, older participants and participants with more advanced disease had increased odds of missingness. There was evidence that data were informatively missing. Additionally, the questionnaire which stated that the sex questions are optional had higher missing data rates. High missing data rates and informatively missing data can lead to biased results. Using the questionnaires that state that they may skip sex items may lead to an underestimation of sexual problems or an overestimation of quality of life.

The identical-twin transfusion syndrome: a source of error in estimating IQ resemblance and heritability.

PubMed

Munsinger, H

1977-01-01

Published studies show that among identical twins, lower birthweight is associated with lower adult intelligence. However, no such relation between birthweight and adult IQ exists among fraternal twins. A likely explanation for the association between birthweight and intelligence among identical twins is the identical twin transfusion syndrome which occurs only between some monochorionic identical twin pairs. The IQ scores from separated identical twins were reanalysed to explore the consequences of identical twin transfusion syndrome for IQ resemblance and heritability. Among 129 published cases of identical twin pairs reared apart, 76 pairs contained some birthweight information. The 76 pairs were separated into three classes: 23 pairs in which there was clear evidence of a substantial birthweight differences (indicating the probable existence of the identical twin transfusion syndrome), 27 pairs in which the information on birthweight was ambiguous (?), and 26 pairs in which there was clear evidence that the twins were similar in birthweight. The reanalyses showed: (1) birthweight differences are positively associated with IQ differences in the total sample of separated identical twins; (2) within the group of 23 twin pairs who showed large birthweight differences, there was a positive relation between birthweight differences and IQ differences; (3) when heritability of IQ is estimated for those twins who do not suffer large birthweight differences, the resemblance (and thus, h2/b) of the separated identical twins' IG is 0-95. Given that the average reliability of the individual IQ test is around 0-95, these data suggest that genetic factors and errors of measurement cause the individual differences in IQ among human beings. Because of the identical twin transfusion syndrome, previous studies of MZ twins have underestimated the effect of genetic factors on IQ. An analysis of the IQs for heavier and lighter birthweight twins suggests that the main effect of the identical twin transfusion syndrome is to lower the IQ of the lighter birthweight twin, rather than to raise the IQ of the more fortunate partner or to influence the IQ of both members. This reanalysis suggests that postnatal cultural and social environment produce little of the total phenotypic variation in IQ found in the normal population. In the future, investigators who use twin studies to estimated heritability must ascertain whether their identical twin pairs suffered from the identical twin transfusion syndrome. Accurate estimates of heritability can only be obtained using identical twins who do not suffer from placental circulation problems. Most likely, the identical twin transfusion syndrome produces anoxia and brain damage during early prenatal development in the smaller identical twin. The anoxia is caused by a lowering of the haemoglobin content of the smaller twin by 35% or more.

An alternative empirical likelihood method in missing response problems and causal inference.

PubMed

Ren, Kaili; Drummond, Christopher A; Brewster, Pamela S; Haller, Steven T; Tian, Jiang; Cooper, Christopher J; Zhang, Biao

2016-11-30

Missing responses are common problems in medical, social, and economic studies. When responses are missing at random, a complete case data analysis may result in biases. A popular debias method is inverse probability weighting proposed by Horvitz and Thompson. To improve efficiency, Robins et al. proposed an augmented inverse probability weighting method. The augmented inverse probability weighting estimator has a double-robustness property and achieves the semiparametric efficiency lower bound when the regression model and propensity score model are both correctly specified. In this paper, we introduce an empirical likelihood-based estimator as an alternative to Qin and Zhang (2007). Our proposed estimator is also doubly robust and locally efficient. Simulation results show that the proposed estimator has better performance when the propensity score is correctly modeled. Moreover, the proposed method can be applied in the estimation of average treatment effect in observational causal inferences. Finally, we apply our method to an observational study of smoking, using data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions clinical trial. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

1.688 g/cm(3) satellite-related repeats: a missing link to dosage compensation and speciation.

PubMed

Gallach, Miguel

2015-09-01

Despite the important progress that has been made on dosage compensation (DC), a critical link in our understanding of the X chromosome recognition mechanisms is still missing. Recent studies in Drosophila indicate that the missing link could be a family of DNA repeats populating the euchromatin of the X chromosome. In this opinion article, I discuss how these findings add a new fresh twist on the DC problem. In the following sections, I first summarize our understanding of DC in Drosophila and integrate these recent discoveries into our knowledge of the X chromosome recognition problem. Next, I introduce a model according to which, 1.688 g/cm(3) satellite-related (SR) repeats would be the primary recognition elements for the dosage compensation complex. Contrary to the current belief, I suggest that the DC system in Drosophila is not conserved and static, but it is continuously co-evolving with the target SR repeats. The potential role of the SR repeats in hybrid incompatibilities and speciation is also discussed. © 2015 John Wiley & Sons Ltd.

[Health status, use of health services and reported morbidity: application of correspondence analysis].

PubMed

Espinàs, J A; Riba, M D; Borràs, J M; Sánchez, V

1995-01-01

The study of the relationship between self-reported morbidity, health status and health care utilization presents methodological problems due to the variety of illnesses and medical conditions that one individual may report. In this article, correspondence analysis was use to analyse these relationships. Data from the Spanish National Health Survey pertaining to the region of Catalonia was studied. Statistical analysis included multi-way correspondence analysis (MCA) followed by cluster analysis. The first factor extracted is defined by self-assessed health perception; the second, by limitation of activities, and the third is related to self-reported morbidity caused by chronic and acute health problems. Fourth and fifth factors, capture residual variability and missing values. Acute problems are more related to perception of poor health while chronic problems are related to perception of fair health. Also, it may be possible to distinguish self-reported morbidity due to relapses of chronic diseases from true acute health problems. Cluster analysis classified individuals into four groups: 1) healthy people; 2) people who assess their health as being poor and those with acute health problems; 3) people with chronic health problems, limited activity and a perception of fair health; and 4) missing values. Correspondence analysis is a useful tool when analyzing qualitative variables like those in a health survey.

Performance of Polygenic Scores for Predicting Phobic Anxiety

PubMed Central

Walter, Stefan; Glymour, M. Maria; Koenen, Karestan; Liang, Liming; Tchetgen Tchetgen, Eric J.; Cornelis, Marilyn; Chang, Shun-Chiao; Rimm, Eric; Kawachi, Ichiro; Kubzansky, Laura D.

2013-01-01

Context Anxiety disorders are common, with a lifetime prevalence of 20% in the U.S., and are responsible for substantial burdens of disability, missed work days and health care utilization. To date, no causal genetic variants have been identified for anxiety, anxiety disorders, or related traits. Objective To investigate whether a phobic anxiety symptom score was associated with 3 alternative polygenic risk scores, derived from external genome-wide association studies of anxiety, an internally estimated agnostic polygenic score, or previously identified candidate genes. Design Longitudinal follow-up study. Using linear and logistic regression we investigated whether phobic anxiety was associated with polygenic risk scores derived from internal, leave-one out genome-wide association studies, from 31 candidate genes, and from out-of-sample genome-wide association weights previously shown to predict depression and anxiety in another cohort. Setting and Participants Study participants (n = 11,127) were individuals from the Nurses' Health Study and Health Professionals Follow-up Study. Main Outcome Measure Anxiety symptoms were assessed via the 8-item phobic anxiety scale of the Crown Crisp Index at two time points, from which a continuous phenotype score was derived. Results We found no genome-wide significant associations with phobic anxiety. Phobic anxiety was also not associated with a polygenic risk score derived from the genome-wide association study beta weights using liberal p-value thresholds; with a previously published genome-wide polygenic score; or with a candidate gene risk score based on 31 genes previously hypothesized to predict anxiety. Conclusion There is a substantial gap between twin-study heritability estimates of anxiety disorders ranging between 20–40% and heritability explained by genome-wide association results. New approaches such as improved genome imputations, application of gene expression and biological pathways information, and incorporating social or environmental modifiers of genetic risks may be necessary to identify significant genetic predictors of anxiety. PMID:24278274

Complex Variation in Measures of General Intelligence and Cognitive Change

PubMed Central

Rowe, Suzanne J.; Rowlatt, Amy; Davies, Gail; Harris, Sarah E.; Porteous, David J.; Liewald, David C.; McNeill, Geraldine; Starr, John M.

2013-01-01

Combining information from multiple SNPs may capture a greater amount of genetic variation than from the sum of individual SNP effects and help identifying missing heritability. Regions may capture variation from multiple common variants of small effect, multiple rare variants or a combination of both. We describe regional heritability mapping of human cognition. Measures of crystallised (gc) and fluid intelligence (gf) in late adulthood (64–79 years) were available for 1806 individuals genotyped for 549,692 autosomal single nucleotide polymorphisms (SNPs). The same individuals were tested at age 11, enabling us the rare opportunity to measure cognitive change across most of their lifespan. 547,750 SNPs ranked by position are divided into 10, 908 overlapping regions of 101 SNPs to estimate the genetic variance each region explains, an approach that resembles classical linkage methods. We also estimate the genetic variation explained by individual autosomes and by SNPs within genes. Empirical significance thresholds are estimated separately for each trait from whole genome scans of 500 permutated data sets. The 5% significance threshold for the likelihood ratio test of a single region ranged from 17–17.5 for the three traits. This is the equivalent to nominal significance under the expectation of a chi-squared distribution (between 1df and 0) of P<1.44×10−5. These thresholds indicate that the distribution of the likelihood ratio test from this type of variance component analysis should be estimated empirically. Furthermore, we show that estimates of variation explained by these regions can be grossly overestimated. After applying permutation thresholds, a region for gf on chromosome 5 spanning the PRRC1 gene is significant at a genome-wide 10% empirical threshold. Analysis of gene methylation on the temporal cortex provides support for the association of PRRC1 and fluid intelligence (P = 0.004), and provides a prime candidate gene for high throughput sequencing of these uniquely informative cohorts. PMID:24349040

The Impact of Population Demography and Selection on the Genetic Architecture of Complex Traits

PubMed Central

Lohmueller, Kirk E.

2014-01-01

Population genetic studies have found evidence for dramatic population growth in recent human history. It is unclear how this recent population growth, combined with the effects of negative natural selection, has affected patterns of deleterious variation, as well as the number, frequency, and effect sizes of mutations that contribute risk to complex traits. Because researchers are performing exome sequencing studies aimed at uncovering the role of low-frequency variants in the risk of complex traits, this topic is of critical importance. Here I use simulations under population genetic models where a proportion of the heritability of the trait is accounted for by mutations in a subset of the exome. I show that recent population growth increases the proportion of nonsynonymous variants segregating in the population, but does not affect the genetic load relative to a population that did not expand. Under a model where a mutation's effect on a trait is correlated with its effect on fitness, rare variants explain a greater portion of the additive genetic variance of the trait in a population that has recently expanded than in a population that did not recently expand. Further, when using a single-marker test, for a given false-positive rate and sample size, recent population growth decreases the expected number of significant associations with the trait relative to the number detected in a population that did not expand. However, in a model where there is no correlation between a mutation's effect on fitness and the effect on the trait, common variants account for much of the additive genetic variance, regardless of demography. Moreover, here demography does not affect the number of significant associations detected. These findings suggest recent population history may be an important factor influencing the power of association tests and in accounting for the missing heritability of certain complex traits. PMID:24875776

Bayesian estimation and use of high-throughput remote sensing indices for quantitative genetic analyses of leaf growth.

PubMed

Baker, Robert L; Leong, Wen Fung; An, Nan; Brock, Marcus T; Rubin, Matthew J; Welch, Stephen; Weinig, Cynthia

2018-02-01

We develop Bayesian function-valued trait models that mathematically isolate genetic mechanisms underlying leaf growth trajectories by factoring out genotype-specific differences in photosynthesis. Remote sensing data can be used instead of leaf-level physiological measurements. Characterizing the genetic basis of traits that vary during ontogeny and affect plant performance is a major goal in evolutionary biology and agronomy. Describing genetic programs that specifically regulate morphological traits can be complicated by genotypic differences in physiological traits. We describe the growth trajectories of leaves using novel Bayesian function-valued trait (FVT) modeling approaches in Brassica rapa recombinant inbred lines raised in heterogeneous field settings. While frequentist approaches estimate parameter values by treating each experimental replicate discretely, Bayesian models can utilize information in the global dataset, potentially leading to more robust trait estimation. We illustrate this principle by estimating growth asymptotes in the face of missing data and comparing heritabilities of growth trajectory parameters estimated by Bayesian and frequentist approaches. Using pseudo-Bayes factors, we compare the performance of an initial Bayesian logistic growth model and a model that incorporates carbon assimilation (A max ) as a cofactor, thus statistically accounting for genotypic differences in carbon resources. We further evaluate two remotely sensed spectroradiometric indices, photochemical reflectance (pri2) and MERIS Terrestrial Chlorophyll Index (mtci) as covariates in lieu of A max , because these two indices were genetically correlated with A max across years and treatments yet allow much higher throughput compared to direct leaf-level gas-exchange measurements. For leaf lengths in uncrowded settings, including A max improves model fit over the initial model. The mtci and pri2 indices also outperform direct A max measurements. Of particular importance for evolutionary biologists and plant breeders, hierarchical Bayesian models estimating FVT parameters improve heritabilities compared to frequentist approaches.

Epigenome-wide association study of fasting measures of glucose, insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network study.

PubMed

Hidalgo, Bertha; Irvin, M Ryan; Sha, Jin; Zhi, Degui; Aslibekyan, Stella; Absher, Devin; Tiwari, Hemant K; Kabagambe, Edmond K; Ordovas, Jose M; Arnett, Donna K

2014-02-01

Known genetic susceptibility loci for type 2 diabetes (T2D) explain only a small proportion of heritable T2D risk. We hypothesize that DNA methylation patterns may contribute to variation in diabetes-related risk factors, and this epigenetic variation across the genome can contribute to the missing heritability in T2D and related metabolic traits. We conducted an epigenome-wide association study for fasting glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) among 837 nondiabetic participants in the Genetics of Lipid Lowering Drugs and Diet Network study, divided into discovery (N = 544) and replication (N = 293) stages. Cytosine guanine dinucleotide (CpG) methylation at ∼470,000 CpG sites was assayed in CD4(+) T cells using the Illumina Infinium HumanMethylation 450 Beadchip. We fit a mixed model with the methylation status of each CpG as the dependent variable, adjusting for age, sex, study site, and T-cell purity as fixed-effects and family structure as a random-effect. A Bonferroni corrected P value of 1.1 × 10(-7) was considered significant in the discovery stage. Significant associations were tested in the replication stage using identical models. Methylation of a CpG site in ABCG1 on chromosome 21 was significantly associated with insulin (P = 1.83 × 10(-7)) and HOMA-IR (P = 1.60 × 10(-9)). Another site in the same gene was significant for HOMA-IR and of borderline significance for insulin (P = 1.29 × 10(-7) and P = 3.36 × 10(-6), respectively). Associations with the top two signals replicated for insulin and HOMA-IR (P = 5.75 × 10(-3) and P = 3.35 × 10(-2), respectively). Our findings suggest that methylation of a CpG site within ABCG1 is associated with fasting insulin and merits further evaluation as a novel disease risk marker.

Familiality and Heritability of Fatigue in an Australian Twin Sample.

PubMed

Corfield, Elizabeth C; Martin, Nicholas G; Nyholt, Dale R

2017-06-01

Familial factors have previously been implicated in the etiology of fatigue, of which a significant proportion is likely attributable to genetic influences. However, family studies have primarily focused on chronic fatigue syndrome, while univariate twin studies have investigated broader fatigue phenotypes. The results for similar fatigue phenotypes vary between studies, particularly with regard to sex-specific contributions to the heritability of the traits. Therefore, the current study aims to investigate the familiality and sex-specific effects of fatigue experienced over the past few weeks in an older Australian population of 660 monozygotic (MZ) twin pairs, 190 MZ singleton twins, 593 dizygotic (DZ) twin pairs, and 365 DZ singleton twins. Higher risks for fatigue were observed in MZ compared to DZ co-twins of probands with fatigue. Univariate heritability analyses indicated fatigue has a significant genetic component, with a heritability (h 2) estimate of 40%. Sex-specific effects did not significantly contribute to the heritability of fatigue, with similar estimates for males (h 2 = 41%, 95% CI [18, 62]) and females (h 2 = 40%, 95% CI [27, 52]). These results indicate that fatigue experienced over the past few weeks has a familial contribution, with additive genetic factors playing an important role in its etiology.

Heritability of decisions and outcomes of public goods games

PubMed Central

Hiraishi, Kai; Shikishima, Chizuru; Yamagata, Shinji; Ando, Juko

2015-01-01

Prosociality is one of the most distinctive features of human beings but there are individual differences in cooperative behavior. Employing the twin method, we examined the heritability of cooperativeness and its outcomes on public goods games using a strategy method. In two experiments (Study 1 and Study 2), twin participants were asked to indicate (1) how much they would contribute to a group when they did not know how much the other group members were contributing, and (2) how much they would contribute if they knew the contributions of others. Overall, the heritability estimates were relatively small for each type of decision, but heritability was greater when participants knew that the others had made larger contributions. Using registered decisions in Study 2, we conducted seven Monte Carlo simulations to examine genetic and environmental influences on the expected game payoffs. For the simulated one-shot game, the heritability estimates were small, comparable to those of game decisions. For the simulated iterated games, we found that the genetic influences first decreased, then increased as the numbers of iterations grew. The implication for the evolution of individual differences in prosociality is discussed. PMID:25954213

Heritability and Familiality of Temperament and Character Dimensions in Korean Families with Schizophrenic Linkage Disequilibrium.

PubMed

Lee, Byung Dae; Park, Je Min; Lee, Young Min; Moon, Eunsoo; Jeong, Hee Jeong; Chung, Young In; Yi, Young Mi

2016-05-31

Categorical syndromes such as schizophrenia may represent complexes of many continuous psychological structural phenotypes along several dimensions of personality development/degeneration. The present study investigated the heritability and familiality of personality dimensions in Korean families with schizophrenic linkage disequilibrium (LD). We recruited 179 probands (with schizophrenia) as well as, whenever possible, their parents and siblings. We used the Temperament and Character Inventory (TCI) to measure personality and symptomatic dimensions. The heritability of personality dimensions in a total of 472 family members was estimated using Sequential Oligogenic Linkage Analysis Routines (SOLAR). To measure familiality, we compared the personality dimensions of family members with those of 336 healthy unrelated controls using analysis of variance (ANOVA) analysis. Three of the seven TCI variables were significantly heritable and were included in subsequent analyses. The three groups (control, unaffected first-degree relative, case) were found to significantly differ from one another, with the expected order of average group scores, for all heritable dimensions. Despite several study limitations with respect to family recruitment and phenotyping, our results show that aberrations in several personality dimensions related to genetic-environment coactions or interactions may underlie the complexity of the schizophrenic syndrome.

Genetic and Environmental Influences on Obesity-Related Phenotypes in Chinese Twins Reared Apart and Together.

PubMed

Zhou, Bin; Gao, Wenjing; Lv, Jun; Yu, Canqing; Wang, Shengfeng; Liao, Chunxiao; Pang, Zengchang; Cong, Liming; Dong, Zhong; Wu, Fan; Wang, Hua; Wu, Xianping; Jiang, Guohong; Wang, Xiaojie; Wang, Binyou; Cao, Weihua; Li, Liming

2015-07-01

The relative importance of genetic and environmental influences on obesity-related phenotypes remains unclear, and few studies have targeted the Chinese population. Here, we used Chinese twins reared apart and together to explore genetic and environmental influences on body mass index (BMI), waist circumference (WC) and waist-height ratio (WHtR), further to differentiate phenotype heritability between different age groups and genders separately and to differentiate influences of rearing environment and correlated environment. Phenotype heritability was calculated using the structural equation model in 11,401 twin pairs aged 25-85 years. BMI (0.70, 95 % confidence interval (CI) 0.66-0.74) of the total population was highly heritable, while WC (0.53, 95 %CI 0.50-0.57) and WHtR (0.48, 95 %CI 0.45-0.51) were moderately heritable. Age and gender stratified analyses found higher heritability in the younger group and males than the older group and females. The correlated environment had a greater influence on the phenotypes than the rearing environment, especially on WC and WHtR, indicating that more correlated environment actions should be taken to prevent the rising trend of abdominal obesity.

Explicating the Conditions Under Which Multilevel Multiple Imputation Mitigates Bias Resulting from Random Coefficient-Dependent Missing Longitudinal Data.

PubMed

Gottfredson, Nisha C; Sterba, Sonya K; Jackson, Kristina M

2017-01-01

Random coefficient-dependent (RCD) missingness is a non-ignorable mechanism through which missing data can arise in longitudinal designs. RCD, for which we cannot test, is a problematic form of missingness that occurs if subject-specific random effects correlate with propensity for missingness or dropout. Particularly when covariate missingness is a problem, investigators typically handle missing longitudinal data by using single-level multiple imputation procedures implemented with long-format data, which ignores within-person dependency entirely, or implemented with wide-format (i.e., multivariate) data, which ignores some aspects of within-person dependency. When either of these standard approaches to handling missing longitudinal data is used, RCD missingness leads to parameter bias and incorrect inference. We explain why multilevel multiple imputation (MMI) should alleviate bias induced by a RCD missing data mechanism under conditions that contribute to stronger determinacy of random coefficients. We evaluate our hypothesis with a simulation study. Three design factors are considered: intraclass correlation (ICC; ranging from .25 to .75), number of waves (ranging from 4 to 8), and percent of missing data (ranging from 20 to 50%). We find that MMI greatly outperforms the single-level wide-format (multivariate) method for imputation under a RCD mechanism. For the MMI analyses, bias was most alleviated when the ICC is high, there were more waves of data, and when there was less missing data. Practical recommendations for handling longitudinal missing data are suggested.

Quantitative Analysis of the Contributing Factors Affecting Specialty Care No-Show Rates at Brooke Army Medical Center

DTIC Science & Technology

2007-03-30

2002). In the Vein Treatment Surgery Center in Texas, failure to properly cancel cosmetic appointments will result in forfeiture of the patients’ $100...appointments. This problem affects more than just the United States. Missed appointments cost the National Healthcare System ( NHS ) in England a...significant amount of money last year. Official figures from the NHS showed 5.7 million appointments were missed in 2004-2005 (Carvel, 2006). When patients

Generalizing MOND to explain the missing mass in galaxy clusters

NASA Astrophysics Data System (ADS)

Hodson, Alistair O.; Zhao, Hongsheng

2017-02-01

Context. MOdified Newtonian Dynamics (MOND) is a gravitational framework designed to explain the astronomical observations in the Universe without the inclusion of particle dark matter. MOND, in its current form, cannot explain the missing mass in galaxy clusters without the inclusion of some extra mass, be it in the form of neutrinos or non-luminous baryonic matter. We investigate whether the MOND framework can be generalized to account for the missing mass in galaxy clusters by boosting gravity in high gravitational potential regions. We examine and review Extended MOND (EMOND), which was designed to increase the MOND scale acceleration in high potential regions, thereby boosting the gravity in clusters. Aims: We seek to investigate galaxy cluster mass profiles in the context of MOND with the primary aim at explaining the missing mass problem fully without the need for dark matter. Methods: Using the assumption that the clusters are in hydrostatic equilibrium, we can compute the dynamical mass of each cluster and compare the result to the predicted mass of the EMOND formalism. Results: We find that EMOND has some success in fitting some clusters, but overall has issues when trying to explain the mass deficit fully. We also investigate an empirical relation to solve the cluster problem, which is found by analysing the cluster data and is based on the MOND paradigm. We discuss the limitations in the text.

Sixteen years of ICPC use in Norwegian primary care: looking through the facts

PubMed Central

2010-01-01

Background The International Classification for Primary Care (ICPC) standard aims to facilitate simultaneous and longitudinal comparisons of clinical primary care practice within and across country borders; it is also used for administrative purposes. This study evaluates the use of the original ICPC-1 and the more complete ICPC-2 Norwegian versions in electronic patient records. Methods We performed a retrospective study of approximately 1.5 million ICPC codes and diagnoses that were collected over a 16-year period at 12 primary care sites in Norway. In the first phase of this period (transition phase, 1992-1999) physicians were allowed to not use an ICPC code in their practice while in the second phase (regular phase, 2000-2008) the use of an ICPC code was mandatory. The ICPC codes and diagnoses defined a problem event for each patient in the PROblem-oriented electronic MEDical record (PROMED). The main outcome measure of our analysis was the percentage of problem events in PROMEDs with inappropriate (or missing) ICPC codes and of diagnoses that did not map the latest ICPC-2 classification. Specific problem areas (pneumonia, anaemia, tonsillitis and diabetes) were examined in the same context. Results Codes were missing in 6.2% of the problem events; incorrect codes were observed in 4.0% of the problem events and text mismatch between the diagnoses and the expected ICPC-2 diagnoses text in 53.8% of the problem events. Missing codes were observed only during the transition phase while incorrect and inappropriate codes were used all over the 16-year period. The physicians created diagnoses that did not exist in ICPC. These 'new' diagnoses were used with varying frequency; many of them were used only once. Inappropriate ICPC-2 codes were also observed in the selected problem areas and for both phases. Conclusions Our results strongly suggest that physicians did not adhere to the ICPC standard due to its incompleteness, i.e. lack of many clinically important diagnoses. This indicates that ICPC is inappropriate for the classification of problem events and the clinical practice in primary care. PMID:20181271

Difficulty eating and significant weight loss in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.

PubMed

Baeza-Velasco, Carolina; Van den Bossche, Thomas; Grossin, Daniel; Hamonet, Claude

2016-06-01

Joint Hypermobility Syndrome, also known as Ehlers-Danlos Syndrome Hypermobility Type (JHS/EDS-HT), is a heritable disorder of connective tissue, common but poorly known by the medical community. Although generalized joint hypermobility and fragility of tissues have been described as core features, recent research highlights the multisystemic nature of JHS/EDS-HT, which presents with a wide range of articular and extra-articular symptoms. Among these, gastrointestinal problems, temporomandibular disorders, and smell and taste abnormalities are common among those affected, having significant implications for eating. The present work reviews the literature linking JHS/EDS-HT and eating problems. Two illustrative case reports, in which JHS/EDS-HT manifestations contribute to developing and maintaining disturbed eating behaviors and significant weight loss, are presented.

Volumetric mammographic density: heritability and association with breast cancer susceptibility loci.

PubMed

Brand, Judith S; Humphreys, Keith; Thompson, Deborah J; Li, Jingmei; Eriksson, Mikael; Hall, Per; Czene, Kamila

2014-12-01

Mammographic density is a strong heritable trait, but data on its genetic component are limited to area-based and qualitative measures. We studied the heritability of volumetric mammographic density ascertained by a fully-automated method and the association with breast cancer susceptibility loci. Heritability of volumetric mammographic density was estimated with a variance component model in a sib-pair sample (N pairs = 955) of a Swedish screening based cohort. Associations with 82 established breast cancer loci were assessed in an independent sample of the same cohort (N = 4025 unrelated women) using linear models, adjusting for age, body mass index, and menopausal status. All tests were two-sided, except for heritability analyses where one-sided tests were used. After multivariable adjustment, heritability estimates (standard error) for percent dense volume, absolute dense volume, and absolute nondense volume were 0.63 (0.06) and 0.43 (0.06) and 0.61 (0.06), respectively (all P < .001). Percent and absolute dense volume were associated with rs10995190 (ZNF365; P = 9.0 × 10(-6) and 8.9 × 10(-7), respectively) and rs9485372 (TAB2; P = 1.8 × 10(-5) and 1.8 × 10(-3), respectively). We also observed associations of rs9383938 (ESR1) and rs2046210 (ESR1) with the absolute dense volume (P = 2.6 × 10(-4) and 4.6 × 10(-4), respectively), and rs6001930 (MLK1) and rs17356907 (NTN4) with the absolute nondense volume (P = 6.7 × 10(-6) and 8.4 × 10(-5), respectively). Our results support the high heritability of mammographic density, though estimates are weaker for absolute than percent dense volume. We also demonstrate that the shared genetic component with breast cancer is not restricted to dense tissues only. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Multi-omics Evidence for Inheritance of Energy Pathways in Red Blood Cells.

PubMed

Weisenhorn, Erin M M; van T Erve, Thomas J; Riley, Nicholas M; Hess, John R; Raife, Thomas J; Coon, Joshua J

2016-12-01

Each year over 90 million units of blood are transfused worldwide. Our dependence on this blood supply mandates optimized blood management and storage. During storage, red blood cells undergo degenerative processes resulting in altered metabolic characteristics which may make blood less viable for transfusion. However, not all stored blood spoils at the same rate, a difference that has been attributed to variable rates of energy usage and metabolism in red blood cells. Specific metabolite abundances are heritable traits; however, the link between heritability of energy metabolism and red blood cell storage profiles is unclear. Herein we performed a comprehensive metabolomics and proteomics study of red blood cells from 18 mono- and di-zygotic twin pairs to measure heritability and identify correlations with ATP and other molecular indices of energy metabolism. Without using affinity-based hemoglobin depletion, our work afforded the deepest multi-omic characterization of red blood cell membranes to date (1280 membrane proteins and 330 metabolites), with 119 membrane protein and 148 metabolite concentrations found to be over 30% heritable. We demonstrate a high degree of heritability in the concentration of energy metabolism metabolites, especially glycolytic metabolites. In addition to being heritable, proteins and metabolites involved in glycolysis and redox metabolism are highly correlated, suggesting that crucial energy metabolism pathways are inherited en bloc at distinct levels. We conclude that individuals can inherit a phenotype composed of higher or lower concentrations of these proteins together. This can result in vastly different red blood cells storage profiles which may need to be considered to develop precise and individualized storage options. Beyond guiding proper blood storage, this intimate link in heritability between energy and redox metabolism pathways may someday prove useful in determining the predisposition of an individual toward metabolic diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Genetic parameters for racing records in trotters using linear and generalized linear models.

PubMed

Suontama, M; van der Werf, J H J; Juga, J; Ojala, M

2012-09-01

Heritability and repeatability and genetic and phenotypic correlations were estimated for trotting race records with linear and generalized linear models using 510,519 records on 17,792 Finnhorses and 513,161 records on 25,536 Standardbred trotters. Heritability and repeatability were estimated for single racing time and earnings traits with linear models, and logarithmic scale was used for racing time and fourth-root scale for earnings to correct for nonnormality. Generalized linear models with a gamma distribution were applied for single racing time and with a multinomial distribution for single earnings traits. In addition, genetic parameters for annual earnings were estimated with linear models on the observed and fourth-root scales. Racing success traits of single placings, winnings, breaking stride, and disqualifications were analyzed using generalized linear models with a binomial distribution. Estimates of heritability were greatest for racing time, which ranged from 0.32 to 0.34. Estimates of heritability were low for single earnings with all distributions, ranging from 0.01 to 0.09. Annual earnings were closer to normal distribution than single earnings. Heritability estimates were moderate for annual earnings on the fourth-root scale, 0.19 for Finnhorses and 0.27 for Standardbred trotters. Heritability estimates for binomial racing success variables ranged from 0.04 to 0.12, being greatest for winnings and least for breaking stride. Genetic correlations among racing traits were high, whereas phenotypic correlations were mainly low to moderate, except correlations between racing time and earnings were high. On the basis of a moderate heritability and moderate to high repeatability for racing time and annual earnings, selection of horses for these traits is effective when based on a few repeated records. Because of high genetic correlations, direct selection for racing time and annual earnings would also result in good genetic response in racing success.

Reading Profiles in Multi-Site Data With Missingness.

PubMed

Eckert, Mark A; Vaden, Kenneth I; Gebregziabher, Mulugeta

2018-01-01

Children with reading disability exhibit varied deficits in reading and cognitive abilities that contribute to their reading comprehension problems. Some children exhibit primary deficits in phonological processing, while others can exhibit deficits in oral language and executive functions that affect comprehension. This behavioral heterogeneity is problematic when missing data prevent the characterization of different reading profiles, which often occurs in retrospective data sharing initiatives without coordinated data collection. Here we show that reading profiles can be reliably identified based on Random Forest classification of incomplete behavioral datasets, after the missForest method is used to multiply impute missing values. Results from simulation analyses showed that reading profiles could be accurately classified across degrees of missingness (e.g., ∼5% classification error for 30% missingness across the sample). The application of missForest to a real multi-site dataset with missingness ( n = 924) showed that reading disability profiles significantly and consistently differed in reading and cognitive abilities for cases with and without missing data. The results of validation analyses indicated that the reading profiles (cases with and without missing data) exhibited significant differences for an independent set of behavioral variables that were not used to classify reading profiles. Together, the results show how multiple imputation can be applied to the classification of cases with missing data and can increase the integrity of results from multi-site open access datasets.

Disease Heritability Inferred from Familial Relationships Reported in Medical Records.

PubMed

Polubriaginof, Fernanda C G; Vanguri, Rami; Quinnies, Kayla; Belbin, Gillian M; Yahi, Alexandre; Salmasian, Hojjat; Lorberbaum, Tal; Nwankwo, Victor; Li, Li; Shervey, Mark M; Glowe, Patricia; Ionita-Laza, Iuliana; Simmerling, Mary; Hripcsak, George; Bakken, Suzanne; Goldstein, David; Kiryluk, Krzysztof; Kenny, Eimear E; Dudley, Joel; Vawdrey, David K; Tatonetti, Nicholas P

2018-05-15

Heritability is essential for understanding the biological causes of disease but requires laborious patient recruitment and phenotype ascertainment. Electronic health records (EHRs) passively capture a wide range of clinically relevant data and provide a resource for studying the heritability of traits that are not typically accessible. EHRs contain next-of-kin information collected via patient emergency contact forms, but until now, these data have gone unused in research. We mined emergency contact data at three academic medical centers and identified 7.4 million familial relationships while maintaining patient privacy. Identified relationships were consistent with genetically derived relatedness. We used EHR data to compute heritability estimates for 500 disease phenotypes. Overall, estimates were consistent with the literature and between sites. Inconsistencies were indicative of limitations and opportunities unique to EHR research. These analyses provide a validation of the use of EHRs for genetics and disease research. Copyright © 2018 Elsevier Inc. All rights reserved.

Heritability analysis of IgG4 antibodies in autoimmune thyroid disease.

PubMed

Outschoorn, I M; Talor, M V; Burek, C L; Hoffman, W H; Rose, N R

2014-08-01

A study of IgG4 autoantibody levels in juvenile thyroid disease patients showed evidence of heritability using the ROMP screening method. These levels increased with time despite the fact that total IgG antibody decreased with time. Evidence of heritability was demonstrated only in patients with high titers of autoantibodies to both thyroglobulin (Tg) and thyroperoxidase (TPO) unlike family members who may show high titers of one or the other and be asymptomatic at the time of sampling. Since high and low IgG4 levels give different heritability plots, these findings may represent a more severe fibrotic form of thyroiditis with a distinct genetic background. Hence a simple predictive approach is offered by this screening tool for the disease in patients and family members which may be helpful in the future to identify IgG4-related thyroiditis early in the course of disease without the requirement for biopsy.

Heritability maps of human face morphology through large-scale automated three-dimensional phenotyping

NASA Astrophysics Data System (ADS)

Tsagkrasoulis, Dimosthenis; Hysi, Pirro; Spector, Tim; Montana, Giovanni

2017-04-01

The human face is a complex trait under strong genetic control, as evidenced by the striking visual similarity between twins. Nevertheless, heritability estimates of facial traits have often been surprisingly low or difficult to replicate. Furthermore, the construction of facial phenotypes that correspond to naturally perceived facial features remains largely a mystery. We present here a large-scale heritability study of face geometry that aims to address these issues. High-resolution, three-dimensional facial models have been acquired on a cohort of 952 twins recruited from the TwinsUK registry, and processed through a novel landmarking workflow, GESSA (Geodesic Ensemble Surface Sampling Algorithm). The algorithm places thousands of landmarks throughout the facial surface and automatically establishes point-wise correspondence across faces. These landmarks enabled us to intuitively characterize facial geometry at a fine level of detail through curvature measurements, yielding accurate heritability maps of the human face (www.heritabilitymaps.info).

Medial Demons Registration Localizes The Degree of Genetic Influence Over Subcortical Shape Variability: An N= 1480 Meta-Analysis

PubMed Central

Gutman, Boris A.; Jahanshad, Neda; Ching, Christopher R.K.; Wang, Yalin; Kochunov, Peter V.; Nichols, Thomas E.; Thompson, Paul M.

2015-01-01

We present a multi-cohort shape heritability study, extending the fast spherical demons registration to subcortical shapes via medial modeling. A multi-channel demons registration based on vector spherical harmonics is applied to medial and curvature features, while controlling for metric distortion. We registered and compared seven subcortical structures of 1480 twins and siblings from the Queensland Twin Imaging Study and Human Connectome Project: Thalamus, Caudate, Putamen, Pallidum, Hippocampus, Amygdala, and Nucleus Accumbens. Radial distance and tensor-based morphometry (TBM) features were found to be highly heritable throughout the entire basal ganglia and limbic system. Surface maps reveal subtle variation in heritability across functionally distinct parts of each structure. Medial Demons reveals more significantly heritable regions than two previously described surface registration methods. This approach may help to prioritize features and measures for genome-wide association studies. PMID:26413211

Medial Demons Registration Localizes The Degree of Genetic Influence Over Subcortical Shape Variability: An N= 1480 Meta-Analysis.

PubMed

Gutman, Boris A; Jahanshad, Neda; Ching, Christopher R K; Wang, Yalin; Kochunov, Peter V; Nichols, Thomas E; Thompson, Paul M

2015-04-01

We present a multi-cohort shape heritability study, extending the fast spherical demons registration to subcortical shapes via medial modeling. A multi-channel demons registration based on vector spherical harmonics is applied to medial and curvature features, while controlling for metric distortion. We registered and compared seven subcortical structures of 1480 twins and siblings from the Queensland Twin Imaging Study and Human Connectome Project: Thalamus, Caudate, Putamen, Pallidum, Hippocampus, Amygdala, and Nucleus Accumbens . Radial distance and tensor-based morphometry (TBM) features were found to be highly heritable throughout the entire basal ganglia and limbic system. Surface maps reveal subtle variation in heritability across functionally distinct parts of each structure. Medial Demons reveals more significantly heritable regions than two previously described surface registration methods. This approach may help to prioritize features and measures for genome-wide association studies.

Interpreting estimates of heritability--a note on the twin decomposition.

PubMed

Stenberg, Anders

2013-03-01

While most outcomes may in part be genetically mediated, quantifying genetic heritability is a different matter. To explore data on twins and decompose the variation is a classical method to determine whether variation in outcomes, e.g. IQ or schooling, originate from genetic endowments or environmental factors. Despite some criticism, the model is still widely used. The critique is generally related to how estimates of heritability may encompass environmental mediation. This aspect is sometimes left implicit by authors even though its relevance for the interpretation is potentially profound. This short note is an appeal for clarity from authors when interpreting the magnitude of heritability estimates. It is demonstrated how disregarding existing theoretical contributions can easily lead to unnecessary misinterpretations and/or controversies. The key arguments are relevant also for estimates based on data of adopted children or from modern molecular genetics research. Copyright © 2012 Elsevier B.V. All rights reserved.

Controlling misses and false alarms in a machine learning framework for predicting uniformity of printed pages

NASA Astrophysics Data System (ADS)

Nguyen, Minh Q.; Allebach, Jan P.

2015-01-01

In our previous work1 , we presented a block-based technique to analyze printed page uniformity both visually and metrically. The features learned from the models were then employed in a Support Vector Machine (SVM) framework to classify the pages into one of the two categories of acceptable and unacceptable quality. In this paper, we introduce a set of tools for machine learning in the assessment of printed page uniformity. This work is primarily targeted to the printing industry, specifically the ubiquitous laser, electrophotographic printer. We use features that are well-correlated with the rankings of expert observers to develop a novel machine learning framework that allows one to achieve the minimum "false alarm" rate, subject to a chosen "miss" rate. Surprisingly, most of the research that has been conducted on machine learning does not consider this framework. During the process of developing a new product, test engineers will print hundreds of test pages, which can be scanned and then analyzed by an autonomous algorithm. Among these pages, most may be of acceptable quality. The objective is to find the ones that are not. These will provide critically important information to systems designers, regarding issues that need to be addressed in improving the printer design. A "miss" is defined to be a page that is not of acceptable quality to an expert observer that the prediction algorithm declares to be a "pass". Misses are a serious problem, since they represent problems that will not be seen by the systems designers. On the other hand, "false alarms" correspond to pages that an expert observer would declare to be of acceptable quality, but which are flagged by the prediction algorithm as "fails". In a typical printer testing and development scenario, such pages would be examined by an expert, and found to be of acceptable quality after all. "False alarm" pages result in extra pages to be examined by expert observers, which increases labor cost. But "false alarms" are not nearly as catastrophic as "misses", which represent potentially serious problems that are never seen by the systems developers. This scenario motivates us to develop a machine learning framework that will achieve the minimum "false alarm" rate subject to a specified "miss" rate. In order to construct such a set of receiver operating characteristic2 (ROC) curves, we examine various tools for the prediction, ranging from an exhaustive search over the space of the nonlinear discriminants to a Cost-Sentitive SVM3 framework. We then compare the curves gained from those methods. Our work shows promise for applying a standard framework to obtain a full ROC curve when it comes to tackling other machine learning problems in industry.

Missing Oral Health-Related Data in the interRAI-HC - Associations with Selected Variables of General Health and the Effect of Multiple Imputation on the Relationship between Oral and General Health.

PubMed

Krausch-Hofmann, Stefanie; Bogaerts, Kris; Hofmann, Michael; de Almeida Mello, Johanna; Fávaro Moreira, Nádia Cristina; Lesaffre, Emmanuel; Declerck, Dominique; Declercq, Anja; Duyck, Joke

2015-01-01

Missing data within the comprehensive geriatric assessment of the interRAI suite of assessment instruments potentially imply the under-detection of conditions that require care as well as the risk of biased statistical results. Impaired oral health in older individuals has to be registered accurately as it causes pain and discomfort and is related to the general health status. This study was based on interRAI-Home Care (HC) baseline data from 7590 subjects (mean age 81.2 years, SD 6.9) in Belgium. It was investigated if missingness of the oral health-related items was associated with selected variables of general health. It was also determined if multiple imputation of missing data affected the associations between oral and general health. Multivariable logistic regression was used to determine if the prevalence of missingness in the oral health-related variables was associated with activities of daily life (ADLH), cognitive performance (CPS2) and depression (DRS). Associations between oral health and ADLH, CPS2 and DRS were determined, with missing data treated by 1. the complete-case technique and 2. by multiple imputation, and results were compared. The individual oral health-related variables had a similar proportion of missing values, ranging from 16.3% to 17.2%. The prevalence of missing data in all oral health-related variables was significantly associated with symptoms of depression (dental prosthesis use OR 1.66, CI 1.41-1.95; damaged teeth OR 1.74, CI 1.48-2.04; chewing problems OR 1.74, CI 1.47-2.05; dry mouth OR 1.65, CI 1.40-1.94). Missingness in damaged teeth (OR 1.27, CI 1.08-1.48), chewing problems (OR 1.22, CI 1.04-1.44) and dry mouth (OR 1.23, CI 1.05-1.44) occurred more frequently in cognitively impaired subjects. ADLH was not associated with the prevalence of missing data. When comparing the complete-case technique with the multiple imputation approach, nearly identical odds ratios characterized the associations between oral and general health. Cognitively impaired and depressive individuals had a higher risk of missing oral health-related information. Associations between oral health and ADLH, CPS2 and DRS were not influenced by multiple imputation of missing data. Further research should concentrate on the mechanisms that mediate the occurrence of missingness to develop preventative strategies.

Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.

PubMed

Codina-Solà, Marta; Rodríguez-Santiago, Benjamín; Homs, Aïda; Santoyo, Javier; Rigau, Maria; Aznar-Laín, Gemma; Del Campo, Miguel; Gener, Blanca; Gabau, Elisabeth; Botella, María Pilar; Gutiérrez-Arumí, Armand; Antiñolo, Guillermo; Pérez-Jurado, Luis Alberto; Cuscó, Ivon

2015-01-01

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders with high heritability. Recent findings support a highly heterogeneous and complex genetic etiology including rare de novo and inherited mutations or chromosomal rearrangements as well as double or multiple hits. We performed whole-exome sequencing (WES) and blood cell transcriptome by RNAseq in a subset of male patients with idiopathic ASD (n = 36) in order to identify causative genes, transcriptomic alterations, and susceptibility variants. We detected likely monogenic causes in seven cases: five de novo (SCN2A, MED13L, KCNV1, CUL3, and PTEN) and two inherited X-linked variants (MAOA and CDKL5). Transcriptomic analyses allowed the identification of intronic causative mutations missed by the usual filtering of WES and revealed functional consequences of some rare mutations. These included aberrant transcripts (PTEN, POLR3C), deregulated expression in 1.7% of mutated genes (that is, SEMA6B, MECP2, ANK3, CREBBP), allele-specific expression (FUS, MTOR, TAF1C), and non-sense-mediated decay (RIT1, ALG9). The analysis of rare inherited variants showed enrichment in relevant pathways such as the PI3K-Akt signaling and the axon guidance. Integrative analysis of WES and blood RNAseq data has proven to be an efficient strategy to identify likely monogenic forms of ASD (19% in our cohort), as well as additional rare inherited mutations that can contribute to ASD risk in a multifactorial manner. Blood transcriptomic data, besides validating 88% of expressed variants, allowed the identification of missed intronic mutations and revealed functional correlations of genetic variants, including changes in splicing, expression levels, and allelic expression.

Heritability of hypothyroidism in the Finnish Hovawart population.

PubMed

Åhlgren, Johanna; Uimari, Pekka

2016-06-07

The Hovawart is a working and companion dog breed of German origin. A few hundred Hovawart dogs are registered annually in Finland. The most common disease with a proposed genetic background in Hovawarts is hypothyroidism. The disease is usually caused by lymphocytic thyroiditis, an autoimmune disorder which destroys the thyroid gland. Hypothyroidism can be treated medically with hormone replacement. Its overall incidence could also be reduced through selection, provided that the trait shows an adequate genetic basis. The aim of this study was to estimate the heritability of hypothyroidism in the Finnish Hovawart population. The pedigree data for the study were provided by the Finnish Kennel Club and the hypothyroidism data by the Finnish Hovawart Club. The data included 4953 dogs born between 1990 and 2010, of which 107 had hypothyroidism and 4846 were unaffected. Prior to the estimation of heritability, we studied the effects of gender, birth year, birth month, and inbreeding on susceptibility to hypothyroidism. Heritability was estimated with the probit model both via restricted maximum likelihood (REML) and Gibbs sampling, using litter and sire of the dog as random effects. None of the studied systematic effects or level of inbreeding had a significant effect on susceptibility to hypothyroidism. The estimated heritability of hypothyroidism varied from 0.47 (SE = 0.18) using REML to 0.62 (SD = 0.21) using Gibbs sampling. Based on our analysis, the heritability of hypothyroidism is moderate to high, suggesting that its prevalence could be decreased through selection. Thus, breeders should notify the breed association of any affected dogs, and their use for breeding should be avoided.

Gating Deficits are More Heritable and Correlate with Increased Clinical Severity in Schizophrenia Patients with a Positive versus Negative Family History

PubMed Central

Greenwood, Tiffany A.; Light, Gregory A.; Swerdlow, Neal R.; Calkins, Monica E.; Green, Michael F.; Gur, Raquel E.; Gur, Ruben C.; Lazzeroni, Laura C.; Nuechterlein, Keith H.; Olincy, Ann; Radant, Allen D.; Seidman, Larry J.; Siever, Larry J.; Silverman, Jeremy M.; Stone, William S.; Sugar, Catherine A.; Tsuang, Debby W.; Tsuang, Ming T.; Turetsky, Bruce I.; Freedman, Robert; Braff, David L.

2016-01-01

Objective The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here we investigated whether gating measures were more heritable in multiply affected families with a positive family history vs. families with only a single affected proband (singleton). Method A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons. Results Both PPI and P50 gating displayed significantly increased heritability in the 97 multiply affected families (47% and 36%, respectively), compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those derived from singleton families. Conclusions PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, which provides further support for the commonality of genes underlying both schizophrenia and gating measures. PMID:26441157

Heritability of Tic Disorders: a Twin-Family Study

PubMed Central

Zilhao, Nuno R.; Olthof, Maria C.; Smit, Dirk J.A.; Cath, Danielle C.; Ligthart, Lannie; Mathews, Carol A.; Delucchi, Kevin; Boomsma, Dorret I.; Dolan, Conor V.

2017-01-01

Background Genetic-epidemiological studies that estimate the contributions of genetic factors to variation in tic symptoms are scarce. We estimated the extent to which genetic and environmental influences contribute to tics, employing various phenotypic definitions ranging between mild and severe symptomatology, in a large population-based adult twin-family sample. Methods In an extended twin-family design, we analyzed lifetime tic data reported by adult mono- and dizygotic twins (n= 8,323) and their family members (n=7,164; parents and siblings) from 7,311 families in the Netherlands Twin Register (NTR). We measured tics by the abbreviated version of the Schedule for Tourette and Other Behavioral Syndromes (STOBS) (TSAICG, 2007). Heritability was estimated by genetic Structural Equation Modeling (SEM) for four tic disorder definitions: three dichotomous and one trichotomous phenotype, characterized by increasingly strictly defined criteria. Results Prevalence rates of the different tic disorders in our sample varied between 0.3 and 4.5% depending on tic disorder definition. Tic frequencies decreased with increasing age. Heritability estimates varied between .25 and .37, depending on phenotypic definitions. None of the phenotypes showed evidence of assortative mating, effects of shared environment, or non-additive genetic effects. Conclusions Heritabilities of mild and severe tic phenotypes were estimated to be moderate. Overlapping confidence intervals of the heritability estimates suggest overlapping genetic liabilities between the various tic phenotypes. The most lenient phenotype (defined only by tic characteristics, excluding criteria B, C and D of DSMIV) rendered sufficiently reliable heritability estimates. These findings have implications in phenotypic definitions for future genetic studies. PMID:27974054

Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study.

PubMed

Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

2013-02-01

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions.

Do genetic factors contribute to the relation between education and metabolic risk factors in young adults? A twin study.

PubMed

Vermeiren, Angelique P A; Bosma, Hans; Gielen, Marij; Lindsey, Patrick J; Derom, Catherine; Vlietinck, Robert; Loos, Ruth J F; Zeegers, Maurice P

2013-12-01

Lower educated people have a higher prevalence of metabolic risk factors (MRF), that is, high waist circumference (WC), high systolic blood pressure, low high-density lipoprotein cholesterol level, high triglycerides and high fasting glucose levels. Behavioural and psychosocial factors cannot fully explain this educational gradient. We aim to examine the possible role of genetic factors by estimating the extent to which education and MRF share a genetic basis and the extent to which the heritability of MRF varies across educational levels. We examined 388 twin pairs, aged 18-34 years, from the Belgian East Flanders Prospective Twin Survey. Using structural equation modelling, a Cholesky bivariate model was applied to assess the shared genetic basis between education and MRF. The heritability of MRF across education levels was estimated using a non-linear multivariate Gaussian regression. Fifteen percent (P < 0.01) of the negative relation between education and WC was because of genes shared between these two traits. Furthermore, the heritability of WC was lower in the lowest educated group (65%) compared with the highest educated group (78%, P = 0.04). The lower heritabilities among the lower educated twins for the other MRF were not significant. The heritability of glucose was higher in the lowest education (80%) group compared with the high education group (67%, P = 0.01). Our findings suggest that genetic factors partly explain educational differences in WC. Furthermore, the lower heritability estimates in WC in the lower educated young adults suggest opportunities for environmental interventions to prevent the development of full-blown metabolic syndrome in middle and older age.

Lack of a heritable reproductive defect in the offspring of male rainbow trout exposed to the environmental estrogen 17α-ethynylestradiol

PubMed Central

Brown, Kim H.; Schultz, Irvin R.; Nagler, James J.

2009-01-01

Endocrine disruptors, including environmental estrogens, have been shown to induce heritable effects through both genetic and epigenetic mechanisms in mammals. Despite this information and the wealth of knowledge regarding the significant reproductive impacts endocrine disruptors impose on fishes, no studies have reported whether the observed effects are heritable. Without this information it is difficult to establish the long-term consequences for exposed populations. To determine potential consequences of long-term effects we must consider the possibility that induced reproductive defects in fishes may be heritable. Using rainbow trout (Oncorhynchus mykiss) as a model this study aims to determine whether a specific reproductive defect observed in 17α-ethynylestradiol exposed male parents, diminished progeny survival, is heritable in the unexposed surviving F1 males. Semen was collected from anesthetized males of the F1 generation upon sexual maturation at two time-points, one year old precocious males and two years old males. In vitro fertilization was used to produce an F2 generation. F2 embryos were then analyzed for survival at 19 days post-fertilization (eye pigmentation) and the different treatment groups statistically compared to the controls. Analysis indicated that F2 offspring survival from F1 males propagated from both exposed and unexposed parents survive normally and no heritable effect was observed in males from the F1 generation for this specific reproductive defect. These results provide scope for the recovery of fish populations exposed to environmental estrogens should the contaminant be removed. PMID:19036459

Heritability of major depressive and comorbid anxiety disorders in multi-generational families at high risk for depression.

PubMed

Guffanti, Guia; Gameroff, Marc J; Warner, Virginia; Talati, Ardesheer; Glatt, Charles E; Wickramaratne, Priya; Weissman, Myrna M

2016-12-01

Family studies have shown that MDD is highly transmittable but have not studied its heritability. Twin studies show heritability of about 40% and do not include anxiety disorders. We assessed heritability of MDD and comorbid anxiety disorders in a multigenerational study of family members at high risk for MDD. In addition, we tested the hypothesis that examined clinical subtypes of MDD defined by early and late age of onset would be under relatively stronger genetic control than broadly defined DSM-IV MDD. The first generation with moderate to severe MDD was recruited from an ambulatory psychiatric treatment setting, and their descendants in the second, third, and fourth generation, were interviewed by clinicians up to six times during a 30-year period. Lifetime rates of MDD and anxiety disorders were collected for 545 participants from 65 multigenerational families. The heritability (h 2 ) of MDD in this high risk sample was estimated at 67%. Anxiety and sequential comorbidity of anxiety disorders and MDD revealed h 2 of 49% and 53%, respectively, and strong positive genetic correlation (rho g  = 0.92, P = 7.3 × 10 -7 ). Early onset MDD did not appear to be under greater genetic control than broadly defined DSM-IV MDD. Individuals who are direct descendants of subjects ascertained for moderate to severe MDD have strong genetic vulnerability to develop anxiety or MDD. Our findings support family based studies as appropriate and useful design to understand the heritability of common disorders such as MDD. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cross-Tissue and Tissue-Specific eQTLs: Partitioning the Heritability of a Complex Trait

PubMed Central

Torres, Jason M.; Gamazon, Eric R.; Parra, Esteban J.; Below, Jennifer E.; Valladares-Salgado, Adan; Wacher, Niels; Cruz, Miguel; Hanis, Craig L.; Cox, Nancy J.

2014-01-01

Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a disproportionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (∼10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index ≥ 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues. PMID:25439722

Estimation of heritability, evolvability and genetic correlations of two pollen and pistil traits involved in a sexual conflict over timing of stigma receptivity in Collinsia heterophylla (Plantaginaceae).

PubMed

Madjidian, Josefin A; Andersson, Stefan; Lankinen, Asa

2012-07-01

Heritable genetic variation is crucial for selection to operate, yet there is a paucity of studies quantifying such variation in interactive male/female sexual traits, especially those of plants. Previous work on the annual plant Collinsia heterophylla, a mixed-mating species, suggests that delayed stigma receptivity is involved in a sexual conflict: pollen from certain donors fertilize ovules earlier than others at the expense of reduced maternal seed set and lower levels of pollen competition. Parent-offspring regressions and sib analyses were performed to test for heritable genetic variation and co-variation in male and female interactive traits related to the sexual conflict. SOME heritable variation and evolvability were found for the female trait (delayed stigma receptivity in presence of pollen), but no evidence was found for genetic variation in the male trait (ability to fertilize ovules early). The results further indicated a marginally significant correlation between a male's ability to fertilize early and early stigma receptivity in offspring. However, despite potential indirect selection of these traits, antagonistic co-evolution may not occur given the lack of heritability of the male trait. To our knowledge, this is the first study of a plant or any hermaphrodite that examines patterns of genetic correlation between two interactive sexual traits, and also the first to assess heritabilities of plant traits putatively involved in a sexual conflict. It is concluded that the ability to delay fertilization in presence of pollen can respond to selection, while the pollen trait has lower evolutionary potential.

Nature or Nurture? Determining the Heritability of Human Striatal Dopamine Function: an [18F]-DOPA PET Study

PubMed Central

Stokes, Paul R A; Shotbolt, Paul; Mehta, Mitul A; Turkheimer, Eric; Benecke, Aaf; Copeland, Caroline; Turkheimer, Federico E; Lingford-Hughes, Anne R; Howes, Oliver D

2013-01-01

Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual-specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions. PMID:23093224

Breast Cancer and Modifiable Lifestyle Factors in Argentinean Women: Addressing Missing Data in a Case-Control Study

PubMed Central

Coquet, Julia Becaria; Tumas, Natalia; Osella, Alberto Ruben; Tanzi, Matteo; Franco, Isabella; Diaz, Maria Del Pilar

2016-01-01

A number of studies have evidenced the effect of modifiable lifestyle factors such as diet, breastfeeding and nutritional status on breast cancer risk. However, none have addressed the missing data problem in nutritional epidemiologic research in South America. Missing data is a frequent problem in breast cancer studies and epidemiological settings in general. Estimates of effect obtained from these studies may be biased, if no appropriate method for handling missing data is applied. We performed Multiple Imputation for missing values on covariates in a breast cancer case-control study of Córdoba (Argentina) to optimize risk estimates. Data was obtained from a breast cancer case control study from 2008 to 2015 (318 cases, 526 controls). Complete case analysis and multiple imputation using chained equations were the methods applied to estimate the effects of a Traditional dietary pattern and other recognized factors associated with breast cancer. Physical activity and socioeconomic status were imputed. Logistic regression models were performed. When complete case analysis was performed only 31% of women were considered. Although a positive association of Traditional dietary pattern and breast cancer was observed from both approaches (complete case analysis OR=1.3, 95%CI=1.0-1.7; multiple imputation OR=1.4, 95%CI=1.2-1.7), effects of other covariates, like BMI and breastfeeding, were only identified when multiple imputation was considered. A Traditional dietary pattern, BMI and breastfeeding are associated with the occurrence of breast cancer in this Argentinean population when multiple imputation is appropriately performed. Multiple Imputation is suggested in Latin America’s epidemiologic studies to optimize effect estimates in the future. PMID:27892664

Harnessing data structure for recovery of randomly missing structural vibration responses time history: Sparse representation versus low-rank structure

NASA Astrophysics Data System (ADS)

Yang, Yongchao; Nagarajaiah, Satish

2016-06-01

Randomly missing data of structural vibration responses time history often occurs in structural dynamics and health monitoring. For example, structural vibration responses are often corrupted by outliers or erroneous measurements due to sensor malfunction; in wireless sensing platforms, data loss during wireless communication is a common issue. Besides, to alleviate the wireless data sampling or communication burden, certain accounts of data are often discarded during sampling or before transmission. In these and other applications, recovery of the randomly missing structural vibration responses from the available, incomplete data, is essential for system identification and structural health monitoring; it is an ill-posed inverse problem, however. This paper explicitly harnesses the data structure itself-of the structural vibration responses-to address this (inverse) problem. What is relevant is an empirical, but often practically true, observation, that is, typically there are only few modes active in the structural vibration responses; hence a sparse representation (in frequency domain) of the single-channel data vector, or, a low-rank structure (by singular value decomposition) of the multi-channel data matrix. Exploiting such prior knowledge of data structure (intra-channel sparse or inter-channel low-rank), the new theories of ℓ1-minimization sparse recovery and nuclear-norm-minimization low-rank matrix completion enable recovery of the randomly missing or corrupted structural vibration response data. The performance of these two alternatives, in terms of recovery accuracy and computational time under different data missing rates, is investigated on a few structural vibration response data sets-the seismic responses of the super high-rise Canton Tower and the structural health monitoring accelerations of a real large-scale cable-stayed bridge. Encouraging results are obtained and the applicability and limitation of the presented methods are discussed.

Contribution of Equal-Sign Instruction beyond Word-Problem Tutoring for Third-Grade Students with Mathematics Difficulty

ERIC Educational Resources Information Center

Powell, Sarah R.; Fuchs, Lynn S.

2010-01-01

Elementary school students often misinterpret the equal sign (=) as an operational rather than a relational symbol. Such misunderstanding is problematic because solving equations with missing numbers may be important for the development of higher order mathematics skills, including solving word problems. Research indicates equal-sign instruction…

Language and Communication-Related Problems of Aviation Safety.

ERIC Educational Resources Information Center

Cushing, Steven

A study of the problems posed by the use of natural language in various aspects of aviation is presented. The study, part of a larger investigation of the feasibility of voice input/output interfaces for communication in aviation, looks at representative real examples of accidents and near misses resulting from language confusions and omissions.…

Addressing the Curriculum Problem in Doctoral Education

ERIC Educational Resources Information Center

Green, Bill

2012-01-01

How best to understand the curriculum problem in doctoral research education: that is the question that this paper engages. It begins by noting that curriculum as such is little referenced and inadequately theorised in higher education and certainly in doctoral education, and indeed has been described as a "missing term". The paper then…

Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS).

PubMed

Fernandez-Pujals, Ana Maria; Adams, Mark James; Thomson, Pippa; McKechanie, Andrew G; Blackwood, Douglas H R; Smith, Blair H; Dominiczak, Anna F; Morris, Andrew D; Matthews, Keith; Campbell, Archie; Linksted, Pamela; Haley, Chris S; Deary, Ian J; Porteous, David J; MacIntyre, Donald J; McIntosh, Andrew M

2015-01-01

The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.

Persons with dementia missing in the community: is it wandering or something unique?

PubMed

Rowe, Meredeth A; Vandeveer, Sydney S; Greenblum, Catherine A; List, Cassandra N; Fernandez, Rachael M; Mixson, Natalie E; Ahn, Hyo C

2011-06-05

At some point in the disease process many persons with dementia (PWD) will have a missing incident and be unable to safely return to their care setting. In previous research studies, researchers have begun to question whether this phenomenon should continue to be called wandering since the antecedents and characteristics of a missing incident are dissimilar to accepted definitions of wandering in dementia. The purpose of this study was to confirm previous findings regarding the antecedents and characteristics of missing incidents, understand the differences between those found dead and alive, and compare the characteristics of a missing incident to that of wandering. A retrospective design was used to analyse 325 newspaper reports of PWD missing in the community. The primary antecedent to a missing incident, particularly in community-dwelling PWD, was becoming lost while conducting a normal and permitted activity alone in the community. The other common antecedent was a lapse in supervision with the expectation that the PWD would remain in a safe location but did not. Deaths most commonly occurred in unpopulated areas due to exposure and drowning. Those who died were found closer to the place last seen and took longer to find, but there were no significant differences in gender or age. The key characteristics of a missing incident were: unpredictable, non-repetitive, temporally appropriate but spatially-disordered, and while using multiple means of movement (walking, car, public transportation). Missing incidents occurred without the discernible pattern present in wandering such as lapping or pacing, repetitive and temporally-disordered. This research supports the mounting evidence that the concept of wandering, in its formal sense, and missing incidents are two distinct concepts. It will be important to further develop the concept of missing incidents by identifying the differences and similarities from wandering. This will allow a more targeted assessment and intervention strategy for each problem.

Persons with dementia missing in the community: Is it wandering or something unique?

PubMed Central

2011-01-01

Background At some point in the disease process many persons with dementia (PWD) will have a missing incident and be unable to safely return to their care setting. In previous research studies, researchers have begun to question whether this phenomenon should continue to be called wandering since the antecedents and characteristics of a missing incident are dissimilar to accepted definitions of wandering in dementia. The purpose of this study was to confirm previous findings regarding the antecedents and characteristics of missing incidents, understand the differences between those found dead and alive, and compare the characteristics of a missing incident to that of wandering. Methods A retrospective design was used to analyse 325 newspaper reports of PWD missing in the community. Results The primary antecedent to a missing incident, particularly in community-dwelling PWD, was becoming lost while conducting a normal and permitted activity alone in the community. The other common antecedent was a lapse in supervision with the expectation that the PWD would remain in a safe location but did not. Deaths most commonly occurred in unpopulated areas due to exposure and drowning. Those who died were found closer to the place last seen and took longer to find, but there were no significant differences in gender or age. The key characteristics of a missing incident were: unpredictable, non-repetitive, temporally appropriate but spatially-disordered, and while using multiple means of movement (walking, car, public transportation). Missing incidents occurred without the discernible pattern present in wandering such as lapping or pacing, repetitive and temporally-disordered. Conclusions This research supports the mounting evidence that the concept of wandering, in its formal sense, and missing incidents are two distinct concepts. It will be important to further develop the concept of missing incidents by identifying the differences and similarities from wandering. This will allow a more targeted assessment and intervention strategy for each problem. PMID:21639942

Developing a framework to review near-miss maternal morbidity in India: a structured review and key stakeholder analysis.

PubMed

Bhattacharyya, Sanghita; Srivastava, Aradhana; Knight, Marian

2014-11-13

In India there is a thrust towards promoting institutional delivery, resulting in problems of overcrowding and compromise to quality of care. Review of near-miss obstetric events has been suggested to be useful to investigate health system functioning, complementing maternal death reviews. The aim of this project was to identify the key elements required for a near-miss review programme for India. A structured review was conducted to identify methods used in assessing near-miss cases. The findings of the structured review were used to develop a suggested framework for conducting near-miss reviews in India. A pool of experts in near-miss review methods in low and middle income countries (LMICs) was identified for vetting the framework developed. Opinions were sought about the feasibility of implementing near-miss reviews in India, the processes to be followed, factors that made implementation successful and the associated challenges. A draft of the framework was revised based on the experts' opinions. Five broad methods of near-miss case review/audit were identified: Facility-based near-miss case review, confidential enquiries, criterion-based clinical audit, structured case review (South African Model) and home-based interviews. The opinion of the 11 stakeholders highlighted that the methods that a facility adopts should depend on the type and number of cases the facility handles, availability and maintenance of a good documentation system, and local leadership and commitment of staff. A proposed framework for conducting near-miss reviews was developed that included a combination of criterion-based clinical audit and near-miss review methods. The approach allowed for development of a framework for researchers and planners seeking to improve quality of maternal care not only at the facility level but also beyond, encompassing community health workers and referral. Further work is needed to evaluate the implementation of this framework to determine its efficacy in improving the quality of care and hence maternal and perinatal morbidity and mortality.

Design, implementation and reporting strategies to reduce the instance and impact of missing patient-reported outcome (PRO) data: a systematic review.

PubMed

Mercieca-Bebber, Rebecca; Palmer, Michael J; Brundage, Michael; Calvert, Melanie; Stockler, Martin R; King, Madeleine T

2016-06-15

Patient-reported outcomes (PROs) provide important information about the impact of treatment from the patients' perspective. However, missing PRO data may compromise the interpretability and value of the findings. We aimed to report: (1) a non-technical summary of problems caused by missing PRO data; and (2) a systematic review by collating strategies to: (A) minimise rates of missing PRO data, and (B) facilitate transparent interpretation and reporting of missing PRO data in clinical research. Our systematic review does not address statistical handling of missing PRO data. MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases (inception to 31 March 2015), and citing articles and reference lists from relevant sources. English articles providing recommendations for reducing missing PRO data rates, or strategies to facilitate transparent interpretation and reporting of missing PRO data were included. 2 reviewers independently screened articles against eligibility criteria. Discrepancies were resolved with the research team. Recommendations were extracted and coded according to framework synthesis. 117 sources (55% discussion papers, 26% original research) met the eligibility criteria. Design and methodological strategies for reducing rates of missing PRO data included: incorporating PRO-specific information into the protocol; carefully designing PRO assessment schedules and defining termination rules; minimising patient burden; appointing a PRO coordinator; PRO-specific training for staff; ensuring PRO studies are adequately resourced; and continuous quality assurance. Strategies for transparent interpretation and reporting of missing PRO data include utilising auxiliary data to inform analysis; transparently reporting baseline PRO scores, rates and reasons for missing data; and methods for handling missing PRO data. The instance of missing PRO data and its potential to bias clinical research can be minimised by implementing thoughtful design, rigorous methodology and transparent reporting strategies. All members of the research team have a responsibility in implementing such strategies. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

A hybrid frame concealment algorithm for H.264/AVC.

PubMed

Yan, Bo; Gharavi, Hamid

2010-01-01

In packet-based video transmissions, packets loss due to channel errors may result in the loss of the whole video frame. Recently, many error concealment algorithms have been proposed in order to combat channel errors; however, most of the existing algorithms can only deal with the loss of macroblocks and are not able to conceal the whole missing frame. In order to resolve this problem, in this paper, we have proposed a new hybrid motion vector extrapolation (HMVE) algorithm to recover the whole missing frame, and it is able to provide more accurate estimation for the motion vectors of the missing frame than other conventional methods. Simulation results show that it is highly effective and significantly outperforms other existing frame recovery methods.

Are Expectations the Missing Link between Life History Strategies and Psychopathology?

PubMed

Kavanagh, Phillip S; Kahl, Bianca L

2018-01-01

Despite advances in knowledge and thinking about using life history theory to explain psychopathology there is still a missing link. That is, we all have a life history strategy, but not all of us develop mental health problems. We propose that the missing link is expectations - a mismatch between expected environmental conditions (including social) set by variations in life history strategies and the current environmental conditions. The mismatch hypothesis has been applied at the biological level in terms of health and disease and we believe that it can also be applied more broadly at the psychological level in terms of perceived expectations in the social environment and the resulting distress-psychopathology-that manifests when our expectations are not met.

Selection-Fusion Approach for Classification of Datasets with Missing Values

PubMed Central

Ghannad-Rezaie, Mostafa; Soltanian-Zadeh, Hamid; Ying, Hao; Dong, Ming

2010-01-01

This paper proposes a new approach based on missing value pattern discovery for classifying incomplete data. This approach is particularly designed for classification of datasets with a small number of samples and a high percentage of missing values where available missing value treatment approaches do not usually work well. Based on the pattern of the missing values, the proposed approach finds subsets of samples for which most of the features are available and trains a classifier for each subset. Then, it combines the outputs of the classifiers. Subset selection is translated into a clustering problem, allowing derivation of a mathematical framework for it. A trade off is established between the computational complexity (number of subsets) and the accuracy of the overall classifier. To deal with this trade off, a numerical criterion is proposed for the prediction of the overall performance. The proposed method is applied to seven datasets from the popular University of California, Irvine data mining archive and an epilepsy dataset from Henry Ford Hospital, Detroit, Michigan (total of eight datasets). Experimental results show that classification accuracy of the proposed method is superior to those of the widely used multiple imputations method and four other methods. They also show that the level of superiority depends on the pattern and percentage of missing values. PMID:20212921

Handling missing Mini-Mental State Examination (MMSE) values: Results from a cross-sectional long-term-care study.

PubMed

Godin, Judith; Keefe, Janice; Andrew, Melissa K

2017-04-01

Missing values are commonly encountered on the Mini Mental State Examination (MMSE), particularly when administered to frail older people. This presents challenges for MMSE scoring in research settings. We sought to describe missingness in MMSEs administered in long-term-care facilities (LTCF) and to compare and contrast approaches to dealing with missing items. As part of the Care and Construction project in Nova Scotia, Canada, LTCF residents completed an MMSE. Different methods of dealing with missing values (e.g., use of raw scores, raw scores/number of items attempted, scale-level multiple imputation [MI], and blended approaches) are compared to item-level MI. The MMSE was administered to 320 residents living in 23 LTCF. The sample was predominately female (73%), and 38% of participants were aged >85 years. At least one item was missing from 122 (38.2%) of the MMSEs. Data were not Missing Completely at Random (MCAR), χ 2 (1110) = 1,351, p < 0.001. Using raw scores for those missing <6 items in combination with scale-level MI resulted in the regression coefficients and standard errors closest to item-level MI. Patterns of missing items often suggest systematic problems, such as trouble with manual dexterity, literacy, or visual impairment. While these observations may be relatively easy to take into account in clinical settings, non-random missingness presents challenges for research and must be considered in statistical analyses. We present suggestions for dealing with missing MMSE data based on the extent of missingness and the goal of analyses. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Evaluation of missing value methods for predicting ambient BTEX concentrations in two neighbouring cities in Southwestern Ontario Canada

NASA Astrophysics Data System (ADS)

Miller, Lindsay; Xu, Xiaohong; Wheeler, Amanda; Zhang, Tianchu; Hamadani, Mariam; Ejaz, Unam

2018-05-01

High density air monitoring campaigns provide spatial patterns of pollutant concentrations which are integral in exposure assessment. Such analysis can assist with the determination of links between air quality and health outcomes, however, problems due to missing data can threaten to compromise these studies. This research evaluates four methods; mean value imputation, inverse distance weighting (IDW), inter-species ratios, and regression, to address missing spatial concentration data ranging from one missing data point up to 50% missing data. BTEX (benzene, toluene, ethylbenzene, and xylenes) concentrations were measured in Windsor and Sarnia, Ontario in the fall of 2005. Concentrations and inter-species ratios were generally similar between the two cities. Benzene (B) was observed to be higher in Sarnia, whereas toluene (T) and the T/B ratios were higher in Windsor. Using these urban, industrialized cities as case studies, this research demonstrates that using inter-species ratios or regression of the data for which there is complete information, along with one measured concentration (i.e. benzene) to predict for missing concentrations (i.e. TEX) results in good agreement between predicted and measured values. In both cities, the general trend remains that best agreement is observed for the leave-one-out scenario, followed by 10% and 25% missing, and the least agreement for the 50% missing cases. In the absence of any known concentrations IDW can provide reasonable agreement between observed and estimated concentrations for the BTEX species, and was superior over mean value imputation which was not able to preserve the spatial trend. The proposed methods can be used to fill in missing data, while preserving the general characteristics and rank order of the data which are sufficient for epidemiologic studies.

A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial

PubMed Central

Rabideau, Dustin J; Nierenberg, Andrew A; Sylvia, Louisa G; Friedman, Edward S.; Bowden, Charles L.; Thase, Michael E.; Ketter, Terence; Ostacher, Michael J.; Reilly-Harrington, Noreen; Iosifescu, Dan V.; Calabrese, Joseph R.; Leon, Andrew C.; Schoenfeld, David A

2014-01-01

Background Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment—Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis [1]. Purpose The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. Methods We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. Results Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. Limitations LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well-specified. Conclusions In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial. PMID:24872362

The treatment of missing data in a large cardiovascular clinical outcomes study.

PubMed

Little, Roderick J; Wang, Julia; Sun, Xiang; Tian, Hong; Suh, Eun-Young; Lee, Michael; Sarich, Troy; Oppenheimer, Leonard; Plotnikov, Alexei; Wittes, Janet; Cook-Bruns, Nancy; Burton, Paul; Gibson, C Michael; Mohanty, Surya

2016-06-01

The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data. A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed. Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions. Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern. © The Author(s) 2016.

[New possibilities will open up in human gene therapy].

PubMed

Portin, Petter

2016-01-01

Gene therapy is divided into somatic and germ line therapy. The latter involves reproductive cells or their stem cells, and its results are heritable. The effects of somatic gene therapy are generally restricted to a single tissue of the patient in question. Until now, all gene therapies in the world have belonged to the regime of somatic therapy, germ line therapy having been a theoretical possibility only. Very recently, however, a method has been developed which is applicable to germ line therapy as well. In addition to technical challenges, severe ethical problems are associated with germ line therapy, demanding opinion statement.

Bone marrow–derived stem cells preserve cone vision in retinitis pigmentosa

PubMed Central

Smith, Lois E.H.

2004-01-01

Retinitis pigmentosa is a heritable group of blinding diseases resulting from loss of photoreceptors, primarily rods and secondarily cones, that mediate central vision. Loss of retinal vasculature is a presumed metabolic consequence of photoreceptor degeneration. A new study shows that autologous bone marrow–derived lineage-negative hematopoietic stem cells, which incorporate into the degenerating blood vessels in two murine models of retinitis pigmentosa, rd1 and rd10, prevent cone loss. The use of autologous bone marrow might avoid problems with rejection while preserving central cone vision in a wide variety of genetically disparate retinal degenerative diseases. PMID:15372096

Heritability of markers of bone metabolism

NASA Technical Reports Server (NTRS)

Smith, Scott M.; Zwart, S. R.; Hargens, A. R.

2005-01-01

Several classic twin studies show genetic effects on markers of bone health, including bone mineral density and parathyroid hormone (PTH). This study was performed to assess the relative contribution of genetics to biochemical markers of bone metabolism. Fifteen sets of identical twins (8 male, 7 female) were housed in a clinical research center where diet was controlled (15% protein, 55% carbohydrate, 30% fat) for 3 consecutive days. Each day, 24-h urine pools were collected and N-telopeptide (NTX), deoxypyridinoline (DPD), calcium, and serum PTH were measured. The broad-sense heritability factor (H2) is an estimation of the portion of the total variance of a given phenotype that is attributable to genetic variance. H2 was estimated from the correlation coefficient of the phenotype data. H2 for NTX was 94% for males and 80% for females, DPD was 88% for males and 97% for females, urinary calcium excretion was 97% for males and 90% for females, and PTH was 92% for males and 79% for females. Since environmental variability was minimized for the 3 days of data collection, these heritability factors are likely overestimated. Nonetheless, the data support the concept that PTH is a predominantly heritable trait, and suggest that NTX, DPD, and calcium excretion are as well. These biochemical data support the previously documented heritability of bone health.

Variation and Heritability in Hair Diameter and Curvature in an Australian Twin Sample.

PubMed

Ho, Yvonne Y W; Brims, Mark; McNevin, Dennis; Spector, Timothy D; Martin, Nicholas G; Medland, Sarah E

2016-08-01

Hair diameter and curvature are two characteristics of human scalp hair used in forensic contexts. While previous data show that subjective categorization of hair curvature is highly heritable, the heritability of objectively measured curvature and diameter, and variability of hair characteristics within each individual have not yet been studied. The present study measured hair diameter and curvature using an optical fiber diameter analyzer in a sample of 2,332 twins and siblings. Heritability was estimated using maximum likelihood structural equation modeling. Results show sex differences in the magnitude of genetic influence for mean diameter and curvature, with the vast majority of the variance accounted for by genetic effects in males (diameter = 86%, curvature = 53%) and females (diameter = 77%, curvature = 61%). The consistency of diameter (variance within an individual) was also highly heritable, but did not show sex limitation, with 68% of the variance accounted for by genetic factors. Moderate phenotypic correlations were seen between diameter and consistency (r = 0.3) but there was little correlation between diameter and curvature (r = -0.13). A bivariate Cholesky analysis was used to estimate the genetic and environmental correlations between hair diameter and consistency, yielding genetic correlations of r gF = 0.27 for females and r gM = 0.25 for males.

Metabolic syndrome-related composite factors over 5 years in the STANISLAS family study: genetic heritability and common environmental influences.

PubMed

Herbeth, Bernard; Samara, Anastasia; Ndiaye, Coumba; Marteau, Jean-Brice; Berrahmoune, Hind; Siest, Gérard; Visvikis-Siest, Sophie

2010-06-03

We estimated genetic heritability and common environmental influences for various traits related to metabolic syndrome in young families from France. At entrance and after 5 years, nineteen traits related to metabolic syndrome were measured in a sample of families drawn from the STANISLAS study. In addition, 5 aggregates of these traits were identified using factor analysis. At entrance, genetic heritability was high (20 to 44%) for plasma lipids and lipoproteins, uric acid, fasting glucose, and the related clusters "risk lipids" and "protective lipids". Intermediate or low genetic heritability (less than 20%) was shown for triglycerides, adiposity indices, blood pressure, hepatic enzyme activity, inflammatory makers and the related clusters: "liver enzymes", "adiposity/blood pressure" and "inflammation". Moreover, common environmental influences were significant for all the parameters. With regard to 5-year changes, polygenic variance was low and not statistically significant for any of the individual variables or clusters whereas shared environment influence was significant. In these young families, genetic heritability of metabolic syndrome-related traits was generally lower than previously reported while the common environmental influences were greater. In addition, only shared environment contributed to short-term changes of these traits. Copyright 2010 Elsevier B.V. All rights reserved.

Heritable variation in host tolerance and resistance inferred from a wild host-parasite system.

PubMed

Mazé-Guilmo, Elise; Loot, Géraldine; Páez, David J; Lefèvre, Thierry; Blanchet, Simon

2014-03-22

Hosts have evolved two distinct defence strategies against parasites: resistance (which prevents infection or limit parasite growth) and tolerance (which alleviates the fitness consequences of infection). However, heritable variation in resistance and tolerance and the genetic correlation between these two traits have rarely been characterized in wild host populations. Here, we estimate these parameters for both traits in Leuciscus burdigalensis, a freshwater fish parasitized by Tracheliastes polycolpus. We used a genetic database to construct a full-sib pedigree in a wild L. burdigalensis population. We then used univariate animal models to estimate inclusive heritability (i.e. all forms of genetic and non-genetic inheritance) in resistance and tolerance. Finally, we assessed the genetic correlation between these two traits using a bivariate animal model. We found significant heritability for resistance (H = 17.6%; 95% CI: 7.2-32.2%) and tolerance (H = 18.8%; 95% CI: 4.4-36.1%), whereas we found no evidence for the existence of a genetic correlation between these traits. Furthermore, we confirm that resistance and tolerance are strongly affected by environmental effects. Our results demonstrate that (i) heritable variation exists for parasite resistance and tolerance in wild host populations, and (ii) these traits can evolve independently in populations.

Bivariate Heritability of Total and Regional Brain Volumes: the Framingham Study

PubMed Central

DeStefano, Anita L.; Seshadri, Sudha; Beiser, Alexa; Atwood, Larry D.; Massaro, Joe M.; Au, Rhoda; Wolf, Philip A.; DeCarli, Charles

2009-01-01

Heritability and genetic and environmental correlations of total and regional brain volumes were estimated from a large, generally healthy, community-based sample, to determine if there are common elements to the genetic influence of brain volumes and white matter hyperintensity volume. There were 1538 Framingham Heart Study participants with brain volume measures from quantitative magnetic resonance imaging (MRI) who were free of stroke and other neurological disorders that might influence brain volumes and who were members of families with at least two Framingham Heart Study participants. Heritability was estimated using variance component methodology and adjusting for the components of the Framingham stroke risk profile. Genetic and environmental correlations between traits were obtained from bivariate analysis. Heritability estimates ranging from 0.46 to 0.60, were observed for total brain, white matter hyperintensity, hippocampal, temporal lobe, and lateral ventricular volumes. Moderate, yet significant, heritability was observed for the other measures. Bivariate analyses demonstrated that relationships between brain volume measures, except for white matter hyperintensity, reflected both moderate to strong shared genetic and shared environmental influences. This study confirms strong genetic effects on brain and white matter hyperintensity volumes. These data extend current knowledge by showing that these two different types of MRI measures do not share underlying genetic or environmental influences. PMID:19812462

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults

PubMed Central

Chen, Fang; He, Jing; Zhang, Jianqi; Chen, Gary K.; Thomas, Venetta; Ambrosone, Christine B.; Bandera, Elisa V.; Berndt, Sonja I.; Bernstein, Leslie; Blot, William J.; Cai, Qiuyin; Carpten, John; Casey, Graham; Chanock, Stephen J.; Cheng, Iona; Chu, Lisa; Deming, Sandra L.; Driver, W. Ryan; Goodman, Phyllis; Hayes, Richard B.; Hennis, Anselm J. M.; Hsing, Ann W.; Hu, Jennifer J.; Ingles, Sue A.; John, Esther M.; Kittles, Rick A.; Kolb, Suzanne; Leske, M. Cristina; Monroe, Kristine R.; Murphy, Adam; Nemesure, Barbara; Neslund-Dudas, Christine; Nyante, Sarah; Ostrander, Elaine A; Press, Michael F.; Rodriguez-Gil, Jorge L.; Rybicki, Ben A.; Schumacher, Fredrick; Stanford, Janet L.; Signorello, Lisa B.; Strom, Sara S.; Stevens, Victoria; Van Den Berg, David; Wang, Zhaoming; Witte, John S.; Wu, Suh-Yuh; Yamamura, Yuko; Zheng, Wei; Ziegler, Regina G.; Stram, Alexander H.; Kolonel, Laurence N.; Marchand, Loïc Le; Henderson, Brian E.; Haiman, Christopher A.; Stram, Daniel O.

2015-01-01

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious. PMID:26125186

Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults.

PubMed

Chen, Fang; He, Jing; Zhang, Jianqi; Chen, Gary K; Thomas, Venetta; Ambrosone, Christine B; Bandera, Elisa V; Berndt, Sonja I; Bernstein, Leslie; Blot, William J; Cai, Qiuyin; Carpten, John; Casey, Graham; Chanock, Stephen J; Cheng, Iona; Chu, Lisa; Deming, Sandra L; Driver, W Ryan; Goodman, Phyllis; Hayes, Richard B; Hennis, Anselm J M; Hsing, Ann W; Hu, Jennifer J; Ingles, Sue A; John, Esther M; Kittles, Rick A; Kolb, Suzanne; Leske, M Cristina; Millikan, Robert C; Monroe, Kristine R; Murphy, Adam; Nemesure, Barbara; Neslund-Dudas, Christine; Nyante, Sarah; Ostrander, Elaine A; Press, Michael F; Rodriguez-Gil, Jorge L; Rybicki, Ben A; Schumacher, Fredrick; Stanford, Janet L; Signorello, Lisa B; Strom, Sara S; Stevens, Victoria; Van Den Berg, David; Wang, Zhaoming; Witte, John S; Wu, Suh-Yuh; Yamamura, Yuko; Zheng, Wei; Ziegler, Regina G; Stram, Alexander H; Kolonel, Laurence N; Le Marchand, Loïc; Henderson, Brian E; Haiman, Christopher A; Stram, Daniel O

2015-01-01

Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.

Childhood socioeconomic status and longitudinal patterns of alcohol problems: Variation across etiological pathways in genetic risk.

PubMed

Barr, Peter B; Silberg, Judy; Dick, Danielle M; Maes, Hermine H

2018-05-14

Childhood socioeconomic status (SES) is an important aspect of early life environment associated with later life health/health behaviors, including alcohol misuse. However, alcohol misuse is modestly heritable and involves differing etiological pathways. Externalizing disorders show significant genetic overlap with substance use, suggesting an impulsivity pathway to alcohol misuse. Alcohol misuse also overlaps with internalizing disorders, suggesting alcohol is used to cope. These differing pathways could lead to different patterns over time and/or differential susceptibility to environmental conditions, such as childhood SES. We examine whether: 1) genetic risk for externalizing and internalizing disorders influence trajectories of alcohol problems across adolescence to adulthood, 2) childhood SES alters genetic risk these disorders on trajectories of alcohol problems, and 3) these patterns are consistent across sex. We find modest evidence of gene-environment interaction. Higher childhood SES increases the risk of alcohol problems in late adolescence/early adulthood, while lower childhood SES increases the risk of alcohol problems in later adulthood, but only among males at greater genetic risk of externalizing disorders. Females from lower SES families with higher genetic risk of internalizing or externalizing disorders have greater risk of developing alcohol problems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Are We Really Missing Small Galaxies?

NASA Astrophysics Data System (ADS)

Kohler, Susanna

2018-02-01

One long-standing astrophysical puzzle is that of so-called missing dwarf galaxies: the number of small dwarf galaxies that we observe is far fewer than that predicted by theory. New simulations, however, suggest that perhaps theres no mystery after all.Missing DwarfsDark-matter cosmological simulations predict many small galaxy halos for every large halo that forms. [The Via Lactea project]Models of a lambda-cold-dark-matter (CDM) universe predict the distribution of galaxy halo sizes throughout the universe, suggesting there should be many more small galaxies than large ones. In what has become known as the missing dwarf problem, however, we find that while we observe the expected numbers of galaxies at the larger end of the scale, we dont see nearly enough small galaxies to match the predictions.Are these galaxies actually missing? Are our predictions wrong? Or are the galaxies there and were just not spotting them? A recent study led by Alyson Brooks (Rutgers University) uses new simulations to explore whatscausing the difference between theory and observation.The fraction of detectable halos as a function of velocity, according to the authors simulations. Below 35 km/s, the detectability of the galaxies drops precipitously. [Brooks et al. 2017]Simulating Galactic VelocitiesBecause we cant weigh a galaxy directly, one proxy used for galaxy mass is its circular velocity; the more massive a galaxy, the faster gas and stars rotate around its center. The discrepancy between models and observations lies in whats known as the galaxy velocity function, which describes the number density of galaxies for a given circular velocity. While theory and observations agree for galaxies with circular velocities above 100 km/s, theory predicts far more dwarfs below this velocity than we observe.To investigate this problem, Brooks and collaborators ran a series of cosmological simulations based on our understanding of a CDM universe. Instead of exploring the result using only dark matter, however, the team included baryons in their simulations. They then produced mock observations of the resulting galaxy velocities to see what an observed velocity function would look like for their simulated galaxies.No Problem After All?Comparison of theoretical velocity functions to observations. The black dashed line shows the original, dark-matter-only model predictions; the black solid line includes the effects of detectability. Blue lines show the authors new model, including the effects of detectability and inclusion of baryons. The red and teal data points from observations match this corrected model well. [Brooks et al. 2017]Based on their baryon-inclusive simulations, Brooks and collaborators argue that there are two main factors that have contributed to the seeming theory/observation mismatch of the missing dwarf problem:Galaxies with low velocities arent detectable by our current surveys.The authors found that the detectable fraction of their simulated galaxies plunges as soon as galaxy velocity drops below 35 km/s. They conclude that were probably unable to see a large fraction of the smallest galaxies.Were not correctly inferring the circular velocity of the galaxies.Circular velocity is usually measured by looking at the line width of a gas tracer like HI. The authors find that this doesnt trace the full potential wells of the dwarf galaxies, however, resulting in an incorrect interpretation of their velocities.The authors show that the inclusion of these effects in the theoretical model significantly changes the predicted shape of the galaxy velocity function. This new function beautifully matches observations, neatly eliminating the missing dwarf problem. Perhaps this long-standing mystery has been a problem of interpretation all along!CitationAlyson M. Brooks et al 2017 ApJ 850 97. doi:10.3847/1538-4357/aa9576

Three challenges described for identifying participants with missing data in trials reports, and potential solutions suggested to systematic reviewers.

PubMed

Akl, Elie A; Kahale, Lara A; Ebrahim, Shanil; Alonso-Coello, Pablo; Schünemann, Holger J; Guyatt, Gordon H

2016-08-01

To categorize the challenges in determining the extent of missing participant data in randomized trials and suggest potential solutions for systematic review authors. During the process of updating a series of Cochrane systematic reviews on the topic of anticoagulation in patients with cancer, we identified challenges and used an iterative approach to improve, and a consensus process to agree on the challenges identified, and to suggest potential ways of dealing with them. The five systematic reviews included 58 trials and 75 meta-analyses for patient-important dichotomous outcomes with 27,037 randomized participants. We identified three categories of challenges: (1) Although systematic reviewers require information about missing data to be reported by outcome, trialists typically report the information by participant; (2) It is not always clear whether the trialists followed up participants in certain categories (e.g., noncompliers), that is, whether some categories of participants did or did not have missing data; (3) It is not always clear how the trialists dealt with missing data in their analysis (e.g., exclusion from the denominator vs. assumptions made for the numerator). We discuss potential solutions for each one of these challenges and suggest further research work. Current reporting of missing data is often not explicit and transparent, and although our potential solutions to problems of suboptimal reporting may be helpful, reliable and valid characterization of the extent and nature of missing data remains elusive. Reporting of missing data in trials needs further improvement. Copyright © 2016 Elsevier Inc. All rights reserved.

Striatal connectivity changes following gambling wins and near-misses: Associations with gambling severity.

PubMed

van Holst, Ruth J; Chase, Henry W; Clark, Luke

2014-01-01

Frontostriatal circuitry is implicated in the cognitive distortions associated with gambling behaviour. 'Near-miss' events, where unsuccessful outcomes are proximal to a jackpot win, recruit overlapping neural circuitry with actual monetary wins. Personal control over a gamble (e.g., via choice) is also known to increase confidence in one's chances of winning (the 'illusion of control'). Using psychophysiological interaction (PPI) analyses, we examined changes in functional connectivity as regular gamblers and non-gambling participants played a slot-machine game that delivered wins, near-misses and full-misses, and manipulated personal control. We focussed on connectivity with striatal seed regions, and associations with gambling severity, using voxel-wise regression. For the interaction term of near-misses (versus full-misses) by personal choice (participant-chosen versus computer-chosen), ventral striatal connectivity with the insula, bilaterally, was positively correlated with gambling severity. In addition, some effects for the contrast of wins compared to all non-wins were observed at an uncorrected (p < .001) threshold: there was an overall increase in connectivity between the striatal seeds and left orbitofrontal cortex and posterior insula, and a negative correlation for gambling severity with the connectivity between the right ventral striatal seed and left anterior cingulate cortex. These findings corroborate the 'non-categorical' nature of reward processing in gambling: near-misses and full-misses are objectively identical outcomes that are processed differentially. Ventral striatal connectivity with the insula correlated positively with gambling severity in the illusion of control contrast, which could be a risk factor for the cognitive distortions and loss-chasing that are characteristic of problem gambling.

Dealing with Divorce

MedlinePlus

... to a serious problem like drinking , abuse, or gambling. Sometimes nothing bad happens, but parents just decide ... distance. Even a quick email saying "I'm thinking of you" helps ease the feelings of missing ...

75 FR 2554 - Advisory Committee on Heritable Disorders in Newborns and Children

Federal Register 2010, 2011, 2012, 2013, 2014

2010-01-15

... FURTHER INFORMATION CONTACT: Ms. Alaina Harris, Genetic Services Branch, Maternal and Child Health Bureau... DEPARTMENT OF HEALTH AND HUMAN SERVICES Health Resources and Services Administration Advisory Committee on Heritable Disorders in Newborns and Children AGENCY: Health Resources and Services...

Heritable and non-heritable genetic effects on retained placenta in Meuse-Rhine-Yssel cattle.

PubMed

Benedictus, L; Koets, A P; Kuijpers, F H J; Joosten, I; van Eldik, P; Heuven, H C M

2013-02-01

Failure of the timely expulsion of the fetal membranes, called retained placenta, leads to reduced fertility, increased veterinary costs and reduced milk yields. The objectives of this study were to concurrently look at the heritable and non-heritable genetic effects on retained placenta and test the hypothesis that a greater coefficient of relationship between dam and calf increases the risk of retained placenta in the dam. The average incidence of retained placenta in 43,661 calvings of Meuse-Rhine-Yssel cattle was 4.5%, ranging from 0% to 29.6% among half-sib groups. The average pedigree based relationship between the sire and the maternal grandsire was 0.05 and ranged from 0 to 1.04. Using a sire-maternal grandsire model the heritability was estimated at 0.22 (SEM=0.07) which is comparable with estimates for other dual purpose breeds. The coefficient of relationship between the sire and the maternal grandsire had an effect on retained placenta. The coefficient of relationship between the sire and the maternal grandsire was used as a proxy for the coefficient of relationship between dam and calf, which is correlated with the probability of major histocompatibility complex (MHC) class I compatibility between dam and calf. MHC class I compatibility is an important risk factor for retained placenta. Although the MHC class I haplotype is genetically determined, MHC class I compatibility is not heritable. This study shows that selection against retained placenta is possible and indicates that preventing the mating of related parents may play a role in the prevention of retained placenta. Copyright © 2012 Elsevier B.V. All rights reserved.

[Genetic study on somatotype of child and adolescent twins in Han nationality].

PubMed

Li, Yu-Ling; Ji, Cheng-Ye; Lu, Shun-Hua; Suo, Li-Ya; Chen, Tian-Jiao

2006-11-01

To assess the genetic and environmental influences on the somatotype of children and adolescents, and the effects of sex and age. The components of somatotype were calculated by using Heather-Cater method in a total of 376 twin pairs of Han nationality, including 245 monozygotic (MZ) and 131 like-sex dizygotic (DZ) twin pairs aged 6 to 18 years. Model-fitting method by Mx package was performed to evaluate the proportion of variance components and to analyze the effects of sex and age on each component of somatotype using the adjusted data for other two somatotype components. The heritability of each component in different development periods divided by growth spurt was also evaluated. The estimated heritabilities of endomorphic, mesomorphic and ectomorphic components were 0.45, 0.80, 0.44 in boys, 0.82, 0.79 and 0.81 in girls respectively after adjusting age. In boys, the heritability of endomorphic component during late puberty was significantly higher than that during pre-puberty (t = 4.99, P < 0.01) and puberty (t = 6.16, P < 0.01), while the heritability of ectomorphic component during late puberty was significantly lower than that during pre-puberty (t = 3.35, P < 0.01) and puberty (t = 4.12, P < 0.01). In girls, the heritability of endomorphic (t = 2.77, P < 0.01) or mesomorphic (t = 2.08, P < 0.05) component during pre-puberty was significantly higher than that in early puberty. The genetic influence on somatotype of girls should be much more than that of boys, especially on the endomorphic and ectomorphic components. For boys, the mesomorphic component is mainly determined by genetic factors, but the other components are mainly affected by environmental ones. The effects of the development periods on the heritability of somatotype should be paid much attention to.

Multi-site study of additive genetic effects on fractional anisotropy of cerebral white matter: Comparing meta and megaanalytical approaches for data pooling.

PubMed

Kochunov, Peter; Jahanshad, Neda; Sprooten, Emma; Nichols, Thomas E; Mandl, René C; Almasy, Laura; Booth, Tom; Brouwer, Rachel M; Curran, Joanne E; de Zubicaray, Greig I; Dimitrova, Rali; Duggirala, Ravi; Fox, Peter T; Hong, L Elliot; Landman, Bennett A; Lemaitre, Hervé; Lopez, Lorna M; Martin, Nicholas G; McMahon, Katie L; Mitchell, Braxton D; Olvera, Rene L; Peterson, Charles P; Starr, John M; Sussmann, Jessika E; Toga, Arthur W; Wardlaw, Joanna M; Wright, Margaret J; Wright, Susan N; Bastin, Mark E; McIntosh, Andrew M; Boomsma, Dorret I; Kahn, René S; den Braber, Anouk; de Geus, Eco J C; Deary, Ian J; Hulshoff Pol, Hilleke E; Williamson, Douglas E; Blangero, John; van 't Ent, Dennis; Thompson, Paul M; Glahn, David C

2014-07-15

Combining datasets across independent studies can boost statistical power by increasing the numbers of observations and can achieve more accurate estimates of effect sizes. This is especially important for genetic studies where a large number of observations are required to obtain sufficient power to detect and replicate genetic effects. There is a need to develop and evaluate methods for joint-analytical analyses of rich datasets collected in imaging genetics studies. The ENIGMA-DTI consortium is developing and evaluating approaches for obtaining pooled estimates of heritability through meta-and mega-genetic analytical approaches, to estimate the general additive genetic contributions to the intersubject variance in fractional anisotropy (FA) measured from diffusion tensor imaging (DTI). We used the ENIGMA-DTI data harmonization protocol for uniform processing of DTI data from multiple sites. We evaluated this protocol in five family-based cohorts providing data from a total of 2248 children and adults (ages: 9-85) collected with various imaging protocols. We used the imaging genetics analysis tool, SOLAR-Eclipse, to combine twin and family data from Dutch, Australian and Mexican-American cohorts into one large "mega-family". We showed that heritability estimates may vary from one cohort to another. We used two meta-analytical (the sample-size and standard-error weighted) approaches and a mega-genetic analysis to calculate heritability estimates across-population. We performed leave-one-out analysis of the joint estimates of heritability, removing a different cohort each time to understand the estimate variability. Overall, meta- and mega-genetic analyses of heritability produced robust estimates of heritability. Copyright © 2014 Elsevier Inc. All rights reserved.

Effects of heritability, shared environment, and nonshared intrauterine conditions on child and adolescent BMI.

PubMed

Salsberry, Pamela J; Reagan, Patricia B

2010-09-01

Heritability studies of BMI, based upon twin samples, have identified genetic and shared environmental components of BMI, but have been largely silent about the nonshared environmental factors. Intrauterine factors have been identified as having significant long-term effects on BMI and may be a critical source of nonshared environmental influence. Extant studies based on samples of either unrelated individuals or twins cannot separate the effects of genetics, shared environments, and nonshared intrauterine conditions because the one lacks variation in the degree of relatedness and the other has insufficient variation in intrauterine conditions. This study improves upon these prior studies by using a large, sibling-based sample to examine heritability, shared environmental, and nonshared intrauterine influences on BMI during two age periods in childhood (6-8 years; 12-14 years). The primary interest was in determining the effects of the intrauterine environment on BMI as a component of the nonshared environment and in determining whether there were sex-specific differences in heritability and/or in the intrauterine factors. These were estimated using regression-based techniques introduced by DeFries and Fulker. Heritability of BMI was estimated to be 0.20-0.28 at 6-8 years and 0.46-0.61 at 12-14 years. Differences in heritability were found at 12-14 years between same-sex as compared to mixed-sex pairs. The shared environmental effect was significant at 6-8 years but insignificant at 12-14 years. Differences in birth weight were significant in all groups at 6-8 years suggesting long-term effects of the nonshared intrauterine environment; at 12-14 years, birth weight was no longer significant for girls.

Heritability of methane emissions from dairy cows over a lactation measured on commercial farms.

PubMed

Pszczola, M; Rzewuska, K; Mucha, S; Strabel, T

2017-11-01

Methane emission is currently an important trait in studies on ruminants due to its environmental and economic impact. Recent studies were based on short-time measurements on individual cows. As methane emission is a longitudinal trait, it is important to investigate its changes over a full lactation. In this study, we aimed to estimate the heritability of the estimated methane emissions from dairy cows using Fourier-transform infrared spectroscopy during milking in an automated milking system by implementing the random regression method. The methane measurements were taken on 485 Polish Holstein-Friesian cows at 2 commercial farms located in western Poland. The overall daily estimated methane emission was 279 g/d. Genetic variance fluctuated over the course of lactation around the average level of 1,509 (g/d), with the highest level, 1,866 (g/d), at the end of the lactation. The permanent environment variance values started at 2,865 (g/d) and then dropped to around 846 (g/d) at 100 d in milk (DIM) to reach the level of 2,444 (g/d) at the end of lactation. The residual variance was estimated at 2,620 (g/d). The average repeatability was 0.25. The heritability level fluctuated over the course of lactation, starting at 0.23 (SE 0.12) and then increasing to its maximum value of 0.3 (SE 0.08) at 212 DIM and ending at the level of 0.27 (SE 0.12). Average heritability was 0.27 (average SE 0.09). We have shown that estimated methane emission is a heritable trait and that the heritability level changes over the course of lactation. The observed changes and low genetic correlations between distant DIM suggest that it may be important to consider the period in which methane phenotypes are collected.

Quantitative trait locus on chromosome 1q influences bone loss in young Mexican American adults

PubMed Central

Shaffer, John R.; Kammerer, Candace M.; Bruder, Jan M.; Cole, Shelley A.; Dyer, Thomas D.; Almasy, Laura; MacCluer, Jean W.; Blangero, John; Bauer, Richard L.; Mitchell, Braxton D.

2009-01-01

Introduction Bone loss occurs as early as the third decade and its cumulative effect throughout adulthood may impact risk for osteoporosis in later life, however the genes and environmental factors influencing early bone loss are largely unknown. We investigated the role of genes in the change in bone mineral density (BMD) in participants of the San Antonio Family Osteoporosis Study. Materials and Methods BMD change in 327 Mexican Americans (ages 25–45 years) from 32 extended pedigrees was calculated from DXA measurements at baseline and follow-up (3.5 to 8.9 years later). Family-based likelihood methods were used to estimate heritability (h2) and perform autosome-wide linkage analysis for BMD change of the proximal femur and forearm, and estimate heritability for BMD change of lumbar spine. Results BMD change was significantly heritable for total hip, ultradistal radius and 33% radius (h2 = 0.34, 0.34, 0.27, respectively, p < 0.03 for all), modestly heritable for femoral neck (h2 = 0.22, p = 0.06) and not heritable for spine BMD. Covariates associated with BMD change included age, sex, baseline BMD, menopause, body mass index, and interim BMI change, and accounted for 6% to 24% of phenotype variation. A significant quantitative trait locus (LOD = 3.6) for femoral neck BMD change was observed on chromosome 1q23. Conclusions We observed that change in BMD in young adults is heritable, and performed one of the first linkage studies for BMD change. Linkage to chromosome 1q23 suggests this region may harbor one or more genes involved in regulating early BMD change of the femoral neck. PMID:19067020

Heritability of climate-relevant traits in a rainforest skink.

PubMed

Martins, Felipe; Kruuk, Loeske; Llewelyn, John; Moritz, Craig; Phillips, Ben

2018-05-22

There is justified concern about the impact of global warming on the persistence of tropical ectotherms. There is also growing evidence for strong selection on climate-relevant physiological traits. Understanding the evolutionary potential of populations is especially important for low dispersal organisms in isolated populations, because these populations have little choice but to adapt. Despite this, direct estimates of heritability and genetic correlations for physiological traits in ectotherms-which will determine their evolutionary responses to selection-are sparse, especially for reptiles. Here we examine the heritabilities and genetic correlations for a set of four morphological and six climate-relevant physiological traits in an isolated population of an Australian rainforest lizard, Lampropholis coggeri. These traits show considerable variation across populations in this species, suggesting local adaptation. From laboratory crosses, we estimated very low to moderate heritability of temperature-related physiological traits (h 2  < 0.31), but significant and higher heritability of desiccation resistance (h 2 ~0.42). These values contrasted with uniformly higher heritabilities (h 2  > 0.51) for morphological traits. At the phenotypic level, there were positive associations among the morphological traits and between thermal limits. Growth rate was positively correlated with thermal limits, but there was no indication that morphology and physiology were linked in any other way. We found some support for a specialist-generalist trade-off in the thermal performance curve, but otherwise there was no evidence for evolutionary constraints, suggesting broadly labile multivariate trait structure. Our results indicate little potential to respond to selection on thermal traits in this population and provide new insights into the capacity of tropical ectotherms to adapt in situ to rapid climate change.

Estimation of heritability for nine common cancers using data from genome-wide association studies in Chinese population.

PubMed

Dai, Juncheng; Shen, Wei; Wen, Wanqing; Chang, Jiang; Wang, Tongmin; Chen, Haitao; Jin, Guangfu; Ma, Hongxia; Wu, Chen; Li, Lian; Song, Fengju; Zeng, YiXin; Jiang, Yue; Chen, Jiaping; Wang, Cheng; Zhu, Meng; Zhou, Wen; Du, Jiangbo; Xiang, Yongbing; Shu, Xiao-Ou; Hu, Zhibin; Zhou, Weiping; Chen, Kexin; Xu, Jianfeng; Jia, Weihua; Lin, Dongxin; Zheng, Wei; Shen, Hongbing

2017-01-15

The familial aggregation indicated the inheritance of cancer risk. Recent genome-wide association studies (GWASs) have identified a number of common single-nucleotide polymorphisms (SNPs). Following heritability analyses have shown that SNPs could explain a moderate amount of variance for different cancer phenotypes among Caucasians. However, little information was available in Chinese population. We performed a genome-wide complex trait analysis for common cancers at nine anatomical sites in Chinese population (14,629 cancer cases vs. 17,554 controls) and estimated the heritability of these cancers based on the common SNPs. We found that common SNPs explained certain amount of heritability with significance for all nine cancer sites: gastric cancer (20.26%), esophageal squamous cell carcinoma (19.86%), colorectal cancer (16.30%), lung cancer (LC) (15.17%), and epithelial ovarian cancer (13.31%), and a similar heritability around 10% for hepatitis B virus-related hepatocellular carcinoma, prostate cancer, breast cancer and nasopharyngeal carcinoma. We found that nearly or less than 25% change was shown when removing the regions expanding 250 kb or 500 kb upward and downward of the GWAS-reported SNPs. We also found strong linear correlations between variance partitioned by each chromosome and chromosomal length only for LC (R 2  = 0.641, p = 0.001) and esophageal squamous cell cancer (R 2  = 0.633, p = 0.002), which implied us the complex heterogeneity of cancers. These results indicate polygenic genetic architecture of the nine common cancers in Chinese population. Further efforts should be made to discover the hidden heritability of different cancer types among Chinese. © 2016 UICC.

Viral genetic variation accounts for a third of variability in HIV-1 set-point viral load in Europe.

PubMed

Blanquart, François; Wymant, Chris; Cornelissen, Marion; Gall, Astrid; Bakker, Margreet; Bezemer, Daniela; Hall, Matthew; Hillebregt, Mariska; Ong, Swee Hoe; Albert, Jan; Bannert, Norbert; Fellay, Jacques; Fransen, Katrien; Gourlay, Annabelle J; Grabowski, M Kate; Gunsenheimer-Bartmeyer, Barbara; Günthard, Huldrych F; Kivelä, Pia; Kouyos, Roger; Laeyendecker, Oliver; Liitsola, Kirsi; Meyer, Laurence; Porter, Kholoud; Ristola, Matti; van Sighem, Ard; Vanham, Guido; Berkhout, Ben; Kellam, Paul; Reiss, Peter; Fraser, Christophe

2017-06-01

HIV-1 set-point viral load-the approximately stable value of viraemia in the first years of chronic infection-is a strong predictor of clinical outcome and is highly variable across infected individuals. To better understand HIV-1 pathogenesis and the evolution of the viral population, we must quantify the heritability of set-point viral load, which is the fraction of variation in this phenotype attributable to viral genetic variation. However, current estimates of heritability vary widely, from 6% to 59%. Here we used a dataset of 2,028 seroconverters infected between 1985 and 2013 from 5 European countries (Belgium, Switzerland, France, the Netherlands and the United Kingdom) and estimated the heritability of set-point viral load at 31% (CI 15%-43%). Specifically, heritability was measured using models of character evolution describing how viral load evolves on the phylogeny of whole-genome viral sequences. In contrast to previous studies, (i) we measured viral loads using standardized assays on a sample collected in a strict time window of 6 to 24 months after infection, from which the viral genome was also sequenced; (ii) we compared 2 models of character evolution, the classical "Brownian motion" model and another model ("Ornstein-Uhlenbeck") that includes stabilising selection on viral load; (iii) we controlled for covariates, including age and sex, which may inflate estimates of heritability; and (iv) we developed a goodness of fit test based on the correlation of viral loads in cherries of the phylogenetic tree, showing that both models of character evolution fit the data well. An overall heritability of 31% (CI 15%-43%) is consistent with other studies based on regression of viral load in donor-recipient pairs. Thus, about a third of variation in HIV-1 virulence is attributable to viral genetic variation.

Heritability and genetic correlation between GERD symptoms severity, metabolic syndrome, and inflammation markers in families living in Mexico City.

PubMed

Reding-Bernal, Arturo; Sánchez-Pedraza, Valentin; Moreno-Macías, Hortensia; Sobrino-Cossio, Sergio; Tejero-Barrera, María Elizabeth; Burguete-García, Ana Isabel; León-Hernández, Mireya; Serratos-Canales, María Fabiola; Duggirala, Ravindranath; López-Alvarenga, Juan Carlos

2017-01-01

The aim of this study was to estimate the heritability (h2) and genetic correlation (ρG) between GERD symptoms severity, metabolic syndrome components, and inflammation markers in Mexican families. Cross-sectional study which included 32 extended families resident in Mexico City. GERD symptoms severity was assessed by the ReQuest in Practice questionnaire. Heritability and genetic correlation were determined using the Sequential Oligogenic Linkage Analysis Routines software. 585 subjects were included, the mean age was 42 (±16.7) years, 57% were women. The heritability of the severity of some GERD symptoms was h2 = 0.27, 0.27, 0.37, and 0.34 (p-value <1.0x10-5) for acidity complaints, lower abdominal complaints, sleep disturbances, and total ReQuest score, respectively. Heritability of metabolic syndrome components ranged from 0.40 for fasting plasma glucose to 0.61 for body mass index and diabetes mellitus. The heritability for fibrinogen and C-reactive protein was 0.64 and 0.38, respectively. Statistically significant genetic correlations were found between acidity complaints and fasting plasma glucose (ρG = 0.40); sleep disturbances and fasting plasma glucose (ρG = 0.36); acidity complaints and diabetes mellitus (ρG = 0.49) and between total ReQuest score and fasting plasma glucose (ρG = 0.43). The rest of metabolic syndrome components did not correlate with GERD symptoms. Genetic factors substantially explain the phenotypic variance of the severity of some GERD symptoms, metabolic syndrome components and inflammation markers. Observed genetic correlations suggest that these phenotypes share common genes. These findings suggest conducting further investigation, as the determination of a linkage analysis in order to identify regions of susceptibility for developing of GERD and metabolic syndrome.

Heritability and genetic correlation between GERD symptoms severity, metabolic syndrome, and inflammation markers in families living in Mexico City

PubMed Central

Reding-Bernal, Arturo; Sánchez-Pedraza, Valentin; Moreno-Macías, Hortensia; Sobrino-Cossio, Sergio; Tejero-Barrera, María Elizabeth; Burguete-García, Ana Isabel; León-Hernández, Mireya; Serratos-Canales, María Fabiola; Duggirala, Ravindranath; López-Alvarenga, Juan Carlos

2017-01-01

Objective The aim of this study was to estimate the heritability (h2) and genetic correlation (ρG) between GERD symptoms severity, metabolic syndrome components, and inflammation markers in Mexican families. Methods Cross-sectional study which included 32 extended families resident in Mexico City. GERD symptoms severity was assessed by the ReQuest in Practice questionnaire. Heritability and genetic correlation were determined using the Sequential Oligogenic Linkage Analysis Routines software. Results 585 subjects were included, the mean age was 42 (±16.7) years, 57% were women. The heritability of the severity of some GERD symptoms was h2 = 0.27, 0.27, 0.37, and 0.34 (p-value <1.0x10-5) for acidity complaints, lower abdominal complaints, sleep disturbances, and total ReQuest score, respectively. Heritability of metabolic syndrome components ranged from 0.40 for fasting plasma glucose to 0.61 for body mass index and diabetes mellitus. The heritability for fibrinogen and C-reactive protein was 0.64 and 0.38, respectively. Statistically significant genetic correlations were found between acidity complaints and fasting plasma glucose (ρG = 0.40); sleep disturbances and fasting plasma glucose (ρG = 0.36); acidity complaints and diabetes mellitus (ρG = 0.49) and between total ReQuest score and fasting plasma glucose (ρG = 0.43). The rest of metabolic syndrome components did not correlate with GERD symptoms. Conclusion Genetic factors substantially explain the phenotypic variance of the severity of some GERD symptoms, metabolic syndrome components and inflammation markers. Observed genetic correlations suggest that these phenotypes share common genes. These findings suggest conducting further investigation, as the determination of a linkage analysis in order to identify regions of susceptibility for developing of GERD and metabolic syndrome. PMID:28582452

Genetic parameters for lamb birth weight, survival and death risk traits.

PubMed

Everett-Hincks, J M; Mathias-Davis, H C; Greer, G J; Auvray, B A; Dodds, K G

2014-07-01

This paper reports genetic parameters for lamb survival and mortality traits on sheep farms in New Zealand. Lamb survival and mortality records were obtained from 38 flocks (103,357 lambs) from 5 yr of lambing data (2007 to 2011) and include many breeds and their crosses (predominantly Romney, Perendale, Coopworth, and Texel). A number of models were tested, all including environmental weather effects and investigating the random environmental effect of dam and litter (dam/year) as well as logit transformation for binary traits. Total heritability (direct + maternal) estimates were low for lamb viability at birth (0.01), lamb death risk to dystocia (0.01), and lamb death risk to starvation exposure (0.01) from birth to 3 d of age in an analysis accounting for direct and maternal genetic effects and the maternal environmental effects. Lamb survival heritabilities reported are very low (total heritabilities range from 0.02 to 0.06). The total heritabilities for the lamb death risk traits are lower than reported estimates of survival to 3 d of age or to weaning suggesting selection for the postmortem traits are not warranted at this time within these flocks. The total heritability for lamb birth weight was moderate (0.38) and the genetic correlations with the lamb death risk traits suggested that directional selection on lamb birth weight would have an effect on survival, although it is likely to have a nonlinear effect and therefore an optimum birth weight at which survival is maximized. This study has also shown that the total heritabilities may be overestimated when not accounting for maternal genetic and environment effects and in particular not accounting for the random environmental effect of litter (dam/year).

The low single nucleotide polymorphism heritability of plasma and saliva cortisol levels.

PubMed

Neumann, Alexander; Direk, Nese; Crawford, Andrew A; Mirza, Saira; Adams, Hieab; Bolton, Jennifer; Hayward, Caroline; Strachan, David P; Payne, Erin K; Smith, Jennifer A; Milaneschi, Yuri; Penninx, Brenda; Hottenga, Jouke J; de Geus, Eco; Oldehinkel, Albertine J; van der Most, Peter J; de Rijke, Yolanda; Walker, Brian R; Tiemeier, Henning

2017-11-01

Cortisol is an important stress hormone affected by a variety of biological and environmental factors, such as the circadian rhythm, exercise and psychological stress. Cortisol is mostly measured using blood or saliva samples. A number of genetic variants have been found to contribute to cortisol levels with these methods. While the effects of several specific single genetic variants is known, the joint genome-wide contribution to cortisol levels is unclear. Our aim was to estimate the amount of cortisol variance explained by common single nucleotide polymorphisms, i.e. the SNP heritability, using a variety of cortisol measures, cohorts and analysis approaches. We analyzed morning plasma (n=5705) and saliva levels (n=1717), as well as diurnal saliva levels (n=1541), in the Rotterdam Study using genomic restricted maximum likelihood estimation. Additionally, linkage disequilibrium score regression was fitted on the results of genome-wide association studies (GWAS) performed by the CORNET consortium on morning plasma cortisol (n=12,597) and saliva cortisol (n=7703). No significant SNP heritability was detected for any cortisol measure, sample or analysis approach. Point estimates ranged from 0% to 9%. Morning plasma cortisol in the CORNET cohorts, the sample with the most power, had a 6% [95%CI: 0-13%] SNP heritability. The results consistently suggest a low SNP heritability of these acute and short-term measures of cortisol. The low SNP heritability may reflect the substantial environmental and, in particular, situational component of these cortisol measures. Future GWAS will require very large sample sizes. Alternatively, more long-term cortisol measures such as hair cortisol samples are needed to discover further genetic pathways regulating cortisol concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

A sibling based design to quantify genetic and shared environmental effects of venous thromboembolism in Sweden.

PubMed

Zöller, Bengt; Ohlsson, Henrik; Sundquist, Jan; Sundquist, Kristina

2017-01-01

Few large studies have examined the heritability of venous thromboembolism (VTE). Moreover, twin studies have been suggested to overestimate heritability. The aim of the present study was to determine the heritability nationwide in the general Swedish population using full siblings and half-siblings. VTE was defined using the Swedish patient register. Full sibling (FS) and half-sibling (HS) pairs born 1950-1990 were obtained from the Swedish Multi-generation Register. A maximum of 5years age difference was allowed. We also required that the individuals within the pair should reside in the same household for at least 8years or not at all (0years) before the youngest turned 16. Information about sibling pair residence within the same household, small residential area, and municipality was obtained from Statistics Sweden. We assumed three potential sources of liability to VTE: additive genetic (A), shared (or common/familial) environment (C), and unique environment (E) components. Totally 881,206 FS pairs and 95,198 HS pairs were included. The full model predicted heritability for VTE with 47% for males and 40% for females. Environmental factors shared by siblings contributed to 0% of the variance in liability for both sexes, and unique environment (E) components accounted for 53% in males and 60% in females. The high heritability of VTE risk indicates that genetic susceptibility plays a substantial role for VTE in the Swedish general population. Overestimation of heritability from twin studies is not likely. The proportion of the variance attributable to shared familial environment factors is small. Subject codes: Genetics, epidemiology, thrombosis, cardiovascular disease, embolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

Accounting for female space sharing in St. Kilda Soay sheep (Ovis aries) results in little change in heritability estimates.

PubMed

Regan, C E; Pilkington, J G; Bérénos, C; Pemberton, J M; Smiseth, P T; Wilson, A J

2017-01-01

When estimating heritability in free-living populations, it is common practice to account for common environment effects, because of their potential to generate phenotypic covariance among relatives thereby biasing heritability estimates. In quantitative genetic studies of natural populations, however, philopatry, which results in relatives being clustered in space, is rarely accounted for. The two studies that have been carried out so far suggest absolute declines in heritability estimates of up to 43% when accounting for space sharing by relatives. However, due to methodological limitations these estimates may not be representative. We used data from the St. Kilda Soay sheep population to estimate heritabilities with and without accounting for space sharing for five traits for which there is evidence for additive genetic variance (birthweight, birth date, lamb August weight, and female post-mortem jaw and metacarpal length). We accounted for space sharing by related females by separately incorporating spatial autocorrelation, and a home range similarity matrix. Although these terms accounted for up to 18% of the variance in these traits, heritability estimates were only reduced by up to 7%. Our results suggest that the bias caused by not accounting for space sharing may be lower than previously thought. This suggests that philopatry does not inevitably lead to a large bias if space sharing by relatives is not accounted for. We hope our work stimulates researchers to model shared space when relatives in their study population share space, as doing so will enable us to better understand when bias may be of particular concern. © 2016 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2016 European Society For Evolutionary Biology.

The Heritability of Mating Behaviour in a Fly and Its Plasticity in Response to the Threat of Sperm Competition

PubMed Central

Bretman, Amanda; Lizé, Anne; Walling, Craig A.; Price, Tom A. R.

2014-01-01

Phenotypic plasticity is a key mechanism by which animals can cope with rapidly changeable environments, but the evolutionary lability of such plasticity remains unclear. The socio-sexual environment can fluctuate very rapidly, affecting both the frequency of mating opportunities and the level of competition males may face. Males of many species show plastic behavioural responses to changes in social environment, in particular the presence of rival males. For example, Drosophila pseudoobscura males respond to rivals by extending mating duration and increasing ejaculate size. Whilst such responses are predicted to be adaptive, the extent to which the magnitude of response is heritable, and hence selectable, is unknown. We investigated this using isofemale lines of the fruit fly D. pseudoobscura, estimating heritability of mating duration in males exposed or not to a rival, and any genetic basis to the change in this trait between these environments (i.e. degree of plasticity). The two populations differed in population sex ratio, and the presence of a sex ratio distorting selfish chromosome. We find that mating duration is heritable, but no evidence of population differences. We find no significant heritability of plasticity in mating duration in one population, but borderline significant heritability of plasticity in the second. This difference between populations might be related to the presence of the sex ratio distorting selfish gene in the latter population, but this will require investigation in additional populations to draw any conclusions. We suggest that there is scope for selection to produce an evolutionary response in the plasticity of mating duration in response to rivals in D. pseudoobscura, at least in some populations. PMID:24587294

The heritability of mating behaviour in a fly and its plasticity in response to the threat of sperm competition.

PubMed

Bretman, Amanda; Lizé, Anne; Walling, Craig A; Price, Tom A R

2014-01-01

Phenotypic plasticity is a key mechanism by which animals can cope with rapidly changeable environments, but the evolutionary lability of such plasticity remains unclear. The socio-sexual environment can fluctuate very rapidly, affecting both the frequency of mating opportunities and the level of competition males may face. Males of many species show plastic behavioural responses to changes in social environment, in particular the presence of rival males. For example, Drosophila pseudoobscura males respond to rivals by extending mating duration and increasing ejaculate size. Whilst such responses are predicted to be adaptive, the extent to which the magnitude of response is heritable, and hence selectable, is unknown. We investigated this using isofemale lines of the fruit fly D. pseudoobscura, estimating heritability of mating duration in males exposed or not to a rival, and any genetic basis to the change in this trait between these environments (i.e. degree of plasticity). The two populations differed in population sex ratio, and the presence of a sex ratio distorting selfish chromosome. We find that mating duration is heritable, but no evidence of population differences. We find no significant heritability of plasticity in mating duration in one population, but borderline significant heritability of plasticity in the second. This difference between populations might be related to the presence of the sex ratio distorting selfish gene in the latter population, but this will require investigation in additional populations to draw any conclusions. We suggest that there is scope for selection to produce an evolutionary response in the plasticity of mating duration in response to rivals in D. pseudoobscura, at least in some populations.

Do the methods used to analyse missing data really matter? An examination of data from an observational study of Intermediate Care patients.

PubMed

Kaambwa, Billingsley; Bryan, Stirling; Billingham, Lucinda

2012-06-27

Missing data is a common statistical problem in healthcare datasets from populations of older people. Some argue that arbitrarily assuming the mechanism responsible for the missingness and therefore the method for dealing with this missingness is not the best option-but is this always true? This paper explores what happens when extra information that suggests that a particular mechanism is responsible for missing data is disregarded and methods for dealing with the missing data are chosen arbitrarily. Regression models based on 2,533 intermediate care (IC) patients from the largest evaluation of IC done and published in the UK to date were used to explain variation in costs, EQ-5D and Barthel index. Three methods for dealing with missingness were utilised, each assuming a different mechanism as being responsible for the missing data: complete case analysis (assuming missing completely at random-MCAR), multiple imputation (assuming missing at random-MAR) and Heckman selection model (assuming missing not at random-MNAR). Differences in results were gauged by examining the signs of coefficients as well as the sizes of both coefficients and associated standard errors. Extra information strongly suggested that missing cost data were MCAR. The results show that MCAR and MAR-based methods yielded similar results with sizes of most coefficients and standard errors differing by less than 3.4% while those based on MNAR-methods were statistically different (up to 730% bigger). Significant variables in all regression models also had the same direction of influence on costs. All three mechanisms of missingness were shown to be potential causes of the missing EQ-5D and Barthel data. The method chosen to deal with missing data did not seem to have any significant effect on the results for these data as they led to broadly similar conclusions with sizes of coefficients and standard errors differing by less than 54% and 322%, respectively. Arbitrary selection of methods to deal with missing data should be avoided. Using extra information gathered during the data collection exercise about the cause of missingness to guide this selection would be more appropriate.

How to deal with missing longitudinal data in cost of illness analysis in Alzheimer's disease-suggestions from the GERAS observational study.

PubMed

Belger, Mark; Haro, Josep Maria; Reed, Catherine; Happich, Michael; Kahle-Wrobleski, Kristin; Argimon, Josep Maria; Bruno, Giuseppe; Dodel, Richard; Jones, Roy W; Vellas, Bruno; Wimo, Anders

2016-07-18

Missing data are a common problem in prospective studies with a long follow-up, and the volume, pattern and reasons for missing data may be relevant when estimating the cost of illness. We aimed to evaluate the effects of different methods for dealing with missing longitudinal cost data and for costing caregiver time on total societal costs in Alzheimer's disease (AD). GERAS is an 18-month observational study of costs associated with AD. Total societal costs included patient health and social care costs, and caregiver health and informal care costs. Missing data were classified as missing completely at random (MCAR), missing at random (MAR) or missing not at random (MNAR). Simulation datasets were generated from baseline data with 10-40 % missing total cost data for each missing data mechanism. Datasets were also simulated to reflect the missing cost data pattern at 18 months using MAR and MNAR assumptions. Naïve and multiple imputation (MI) methods were applied to each dataset and results compared with complete GERAS 18-month cost data. Opportunity and replacement cost approaches were used for caregiver time, which was costed with and without supervision included and with time for working caregivers only being costed. Total costs were available for 99.4 % of 1497 patients at baseline. For MCAR datasets, naïve methods performed as well as MI methods. For MAR, MI methods performed better than naïve methods. All imputation approaches were poor for MNAR data. For all approaches, percentage bias increased with missing data volume. For datasets reflecting 18-month patterns, a combination of imputation methods provided more accurate cost estimates (e.g. bias: -1 % vs -6 % for single MI method), although different approaches to costing caregiver time had a greater impact on estimated costs (29-43 % increase over base case estimate). Methods used to impute missing cost data in AD will impact on accuracy of cost estimates although varying approaches to costing informal caregiver time has the greatest impact on total costs. Tailoring imputation methods to the reason for missing data will further our understanding of the best analytical approach for studies involving cost outcomes.

Teachers' and Students' Perceptions of Students' Problem-Solving Difficulties in Physics: Implications for Remediation

ERIC Educational Resources Information Center

Ogunleye, Ayodele O.

2009-01-01

In recent times, science education researchers have identified a lot of instruments for evaluating conceptual understanding as well as students' attitudes and beliefs about physics; unfortunately however, there are no broad based evaluation instruments in the field of problem-solving in physics. This missing tool is an indication of the complexity…

Factors Contributing to the Problem of Student Absenteeism in a Rural School

ERIC Educational Resources Information Center

Durborow, Angela

2017-01-01

Student attendance would seem to be a vital link in measuring student success in school. If students are not in school, they miss instruction from the teacher. Without instruction it seems incredibly difficult to complete the work needed to pass classes and be successful in school. The research explored the problem of practice of student…

Correlation of Electronic Health Records Use and Reduced Prevalence of Diabetes Co-Morbidities

ERIC Educational Resources Information Center

Eller, James D.

2013-01-01

The general problem is Native American tribes have high prevalence rates of diabetes. The specific problem is the failure of IHS sites to adopt EHR may cause health care providers to miss critical opportunities to improve screening and triage processes that result in quality improvement. The purpose of the quantitative correlational study was to…

Mental health workers. Graduation daze.

PubMed

Lewis, Carol

2003-09-11

PCTs are likely to miss the national target on employment of graduate mental health workers. Pilots are showing success in reducing referrals. Managers must address career progression problems and define roles more clearly.

Dentistry to the rescue of missing children: A review.

PubMed

Vij, Nitika; Kochhar, Gulsheen Kaur; Chachra, Sanjay; Kaur, Taranjot

2016-01-01

Today's society is becoming increasingly unsafe for children: we frequently hear about new incidents of missing children, which lead to emotional trauma for the loved ones and expose systemic failures of law and order. Parents can take extra precautions to ensure the safety of their children by educating them about ways to protect themselves and keep important records of the child such as updated color photographs, fingerprints, deoxyribonucleic acid (DNA) samples, etc., handy. However, in spite of all efforts, the problem of missing children still remains. Developments in the field of dentistry have empowered dentists with various tools and techniques to play a pivotal role in tracing a missing child. One such tool is Toothprints, a patented arch-shaped thermoplastic dental impression wafer developed by Dr. David Tesini, a paediatric dentist from Massachusetts. Toothprints enables a unique identification of the missing children not only through the bite impression but also through salivary DNA. Besides the use of Toothprints, a dentist can assist investigating agencies in identifying the missing children in multiple ways, including postmortem dental profiling, labeled dental fixtures, DNA extraction from teeth, and serial number engraving on the children's teeth. More importantly, all these tools cause minimal inconvenience to the individual, making a dentist's role in tracking a missing child even more significant. Thus, the simple discipline of maintaining timely dental records with the help of their dentists can save potential hassles for the parents in the future.

Congenitally missing teeth (hypodontia): A review of the literature concerning the etiology, prevalence, risk factors, patterns and treatment

PubMed Central

Rakhshan, Vahid

2015-01-01

Congenitally missing teeth (CMT), or as usually called hypodontia, is a highly prevalent and costly dental anomaly. Besides an unfavorable appearance, patients with missing teeth may suffer from malocclusion, periodontal damage, insufficient alveolar bone growth, reduced chewing ability, inarticulate pronunciation and other problems. Treatment might be usually expensive and multidisciplinary. This highly frequent and yet expensive anomaly is of interest to numerous clinical, basic science and public health fields such as orthodontics, pediatric dentistry, prosthodontics, periodontics, maxillofacial surgery, anatomy, anthropology and even the insurance industry. This essay reviews the findings on the etiology, prevalence, risk factors, occurrence patterns, skeletal changes and treatments of congenitally missing teeth. It seems that CMT usually appears in females and in the permanent dentition. It is not conclusive whether it tends to occur more in the maxilla or mandible and also in the anterior versus posterior segments. It can accompany various complications and should be attended by expert teams as soon as possible. PMID:25709668

On the Use of Local Assessments for Monitoring Centrally Reviewed Endpoints with Missing Data in Clinical Trials*

PubMed Central

Brummel, Sean S.; Gillen, Daniel L.

2014-01-01

Due to ethical and logistical concerns it is common for data monitoring committees to periodically monitor accruing clinical trial data to assess the safety, and possibly efficacy, of a new experimental treatment. When formalized, monitoring is typically implemented using group sequential methods. In some cases regulatory agencies have required that primary trial analyses should be based solely on the judgment of an independent review committee (IRC). The IRC assessments can produce difficulties for trial monitoring given the time lag typically associated with receiving assessments from the IRC. This results in a missing data problem wherein a surrogate measure of response may provide useful information for interim decisions and future monitoring strategies. In this paper, we present statistical tools that are helpful for monitoring a group sequential clinical trial with missing IRC data. We illustrate the proposed methodology in the case of binary endpoints under various missingness mechanisms including missing completely at random assessments and when missingness depends on the IRC’s measurement. PMID:25540717

Estimating Interaction Effects With Incomplete Predictor Variables

PubMed Central

Enders, Craig K.; Baraldi, Amanda N.; Cham, Heining

2014-01-01

The existing missing data literature does not provide a clear prescription for estimating interaction effects with missing data, particularly when the interaction involves a pair of continuous variables. In this article, we describe maximum likelihood and multiple imputation procedures for this common analysis problem. We outline 3 latent variable model specifications for interaction analyses with missing data. These models apply procedures from the latent variable interaction literature to analyses with a single indicator per construct (e.g., a regression analysis with scale scores). We also discuss multiple imputation for interaction effects, emphasizing an approach that applies standard imputation procedures to the product of 2 raw score predictors. We thoroughly describe the process of probing interaction effects with maximum likelihood and multiple imputation. For both missing data handling techniques, we outline centering and transformation strategies that researchers can implement in popular software packages, and we use a series of real data analyses to illustrate these methods. Finally, we use computer simulations to evaluate the performance of the proposed techniques. PMID:24707955

Freezability genetics in rabbit semen.

PubMed

Lavara, R; Mocé, E; Baselga, M; Vicente, J S

2017-10-15

The aim of this study was to estimate the heritability of semen freezability and to estimate the genetic correlation between frozen-thawed sperm traits and the growth rate in a paternal rabbit line. Estimated heritabilities showed that frozen-thawed semen traits are heritable (ranged between 0.08 and 0.15). In the case of Live-FT (percentage of viable sperm after freezing), the estimated heritability is the highest one, and suggests the possibility of effective selection. After the study of genetic correlations it seems that daily weight gain (DG) was negatively correlated with sperm freezability, but no further conclusions could be drawn due to the high HPD95%. More data should be included in order to obtain better accuracy for the estimates of these genetic correlations. If the results obtained at present study were confirmed, it would imply that selection for DG could alter sperm cell membranes or seminal plasma composition, both components related to sperm cryoresistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994.

PubMed

Jelenkovic, Aline; Hur, Yoon-Mi; Sund, Reijo; Yokoyama, Yoshie; Siribaddana, Sisira H; Hotopf, Matthew; Sumathipala, Athula; Rijsdijk, Fruhling; Tan, Qihua; Zhang, Dongfeng; Pang, Zengchang; Aaltonen, Sari; Heikkilä, Kauko; Öncel, Sevgi Y; Aliev, Fazil; Rebato, Esther; Tarnoki, Adam D; Tarnoki, David L; Christensen, Kaare; Skytthe, Axel; Kyvik, Kirsten O; Silberg, Judy L; Eaves, Lindon J; Maes, Hermine H; Cutler, Tessa L; Hopper, John L; Ordoñana, Juan R; Sánchez-Romera, Juan F; Colodro-Conde, Lucia; Cozen, Wendy; Hwang, Amie E; Mack, Thomas M; Sung, Joohon; Song, Yun-Mi; Yang, Sarah; Lee, Kayoung; Franz, Carol E; Kremen, William S; Lyons, Michael J; Busjahn, Andreas; Nelson, Tracy L; Whitfield, Keith E; Kandler, Christian; Jang, Kerry L; Gatz, Margaret; Butler, David A; Stazi, Maria A; Fagnani, Corrado; D'Ippolito, Cristina; Duncan, Glen E; Buchwald, Dedra; Derom, Catherine A; Vlietinck, Robert F; Loos, Ruth Jf; Martin, Nicholas G; Medland, Sarah E; Montgomery, Grant W; Jeong, Hoe-Uk; Swan, Gary E; Krasnow, Ruth; Magnusson, Patrik Ke; Pedersen, Nancy L; Dahl-Aslan, Anna K; McAdams, Tom A; Eley, Thalia C; Gregory, Alice M; Tynelius, Per; Baker, Laura A; Tuvblad, Catherine; Bayasgalan, Gombojav; Narandalai, Danshiitsoodol; Lichtenstein, Paul; Spector, Timothy D; Mangino, Massimo; Lachance, Genevieve; Bartels, Meike; van Beijsterveldt, Toos Cem; Willemsen, Gonneke; Burt, S Alexandra; Klump, Kelly L; Harris, Jennifer R; Brandt, Ingunn; Nilsen, Thomas Sevenius; Krueger, Robert F; McGue, Matt; Pahlen, Shandell; Corley, Robin P; Hjelmborg, Jacob V B; Goldberg, Jack H; Iwatani, Yoshinori; Watanabe, Mikio; Honda, Chika; Inui, Fujio; Rasmussen, Finn; Huibregtse, Brooke M; Boomsma, Dorret I; Sørensen, Thorkild I A; Kaprio, Jaakko; Silventoinen, Karri

2016-12-14

Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886-1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.

Lineage Tracking for Probing Heritable Phenotypes at Single-Cell Resolution

PubMed Central

Cottinet, Denis; Condamine, Florence; Bremond, Nicolas; Griffiths, Andrew D.; Rainey, Paul B.; de Visser, J. Arjan G. M.; Baudry, Jean; Bibette, Jérôme

2016-01-01

Determining the phenotype and genotype of single cells is central to understand microbial evolution. DNA sequencing technologies allow the detection of mutants at high resolution, but similar approaches for phenotypic analyses are still lacking. We show that a drop-based millifluidic system enables the detection of heritable phenotypic changes in evolving bacterial populations. At time intervals, cells were sampled and individually compartmentalized in 100 nL drops. Growth through 15 generations was monitored using a fluorescent protein reporter. Amplification of heritable changes–via growth–over multiple generations yields phenotypically distinct clusters reflecting variation relevant for evolution. To demonstrate the utility of this approach, we follow the evolution of Escherichia coli populations during 30 days of starvation. Phenotypic diversity was observed to rapidly increase upon starvation with the emergence of heritable phenotypes. Mutations corresponding to each phenotypic class were identified by DNA sequencing. This scalable lineage-tracking technology opens the door to large-scale phenotyping methods with special utility for microbiology and microbial population biology. PMID:27077662

Lineage Tracking for Probing Heritable Phenotypes at Single-Cell Resolution.

PubMed

Cottinet, Denis; Condamine, Florence; Bremond, Nicolas; Griffiths, Andrew D; Rainey, Paul B; de Visser, J Arjan G M; Baudry, Jean; Bibette, Jérôme

2016-01-01

Determining the phenotype and genotype of single cells is central to understand microbial evolution. DNA sequencing technologies allow the detection of mutants at high resolution, but similar approaches for phenotypic analyses are still lacking. We show that a drop-based millifluidic system enables the detection of heritable phenotypic changes in evolving bacterial populations. At time intervals, cells were sampled and individually compartmentalized in 100 nL drops. Growth through 15 generations was monitored using a fluorescent protein reporter. Amplification of heritable changes-via growth-over multiple generations yields phenotypically distinct clusters reflecting variation relevant for evolution. To demonstrate the utility of this approach, we follow the evolution of Escherichia coli populations during 30 days of starvation. Phenotypic diversity was observed to rapidly increase upon starvation with the emergence of heritable phenotypes. Mutations corresponding to each phenotypic class were identified by DNA sequencing. This scalable lineage-tracking technology opens the door to large-scale phenotyping methods with special utility for microbiology and microbial population biology.

A test of the facultative calibration/reactive heritability model of extraversion

PubMed Central

Haysom, Hannah J.; Mitchem, Dorian G.; Lee, Anthony J.; Wright, Margaret J.; Martin, Nicholas G.; Keller, Matthew C.; Zietsch, Brendan P.

2015-01-01

A model proposed by Lukaszewski and Roney (2011) suggests that each individual’s level of extraversion is calibrated to other traits that predict the success of an extraverted behavioural strategy. Under ‘facultative calibration’, extraversion is not directly heritable, but rather exhibits heritability through its calibration to directly heritable traits (“reactive heritability”). The current study uses biometrical modelling of 1659 identical and non-identical twins and their siblings to assess whether the genetic variation in extraversion is calibrated to variation in facial attractiveness, intelligence, height in men and body mass index (BMI) in women. Extraversion was significantly positively correlated with facial attractiveness in both males (r=.11) and females (r=.18), but correlations between extraversion and the other variables were not consistent with predictions. Further, twin modelling revealed that the genetic variation in facial attractiveness did not account for a substantial proportion of the variation in extraversion in either males (2.4%) or females (0.5%). PMID:26880866

Heritable temperament pathways to early callous-unemotional behaviour.

PubMed

Waller, Rebecca; Trentacosta, Christopher J; Shaw, Daniel S; Neiderhiser, Jenae M; Ganiban, Jody M; Reiss, David; Leve, Leslie D; Hyde, Luke W

2016-12-01

Early callous-unemotional behaviours identify children at risk for antisocial behaviour. Recent work suggests that the high heritability of callous-unemotional behaviours is qualified by interactions with positive parenting. To examine whether heritable temperament dimensions of fearlessness and low affiliative behaviour are associated with early callous-unemotional behaviours and whether parenting moderates these associations. Using an adoption sample (n = 561), we examined pathways from biological mother self-reported fearlessness and affiliative behaviour to child callous-unemotional behaviours via observed child fearlessness and affiliative behaviour, and whether adoptive parent observed positive parenting moderated pathways. Biological mother fearlessness predicted child callous-unemotional behaviours via earlier child fearlessness. Biological mother low affiliative behaviour predicted child callous-unemotional behaviours, although not via child affiliative behaviours. Adoptive mother positive parenting moderated the fearlessness to callous-unemotional behaviour pathway. Heritable fearlessness and low interpersonal affiliation traits contribute to the development of callous-unemotional behaviours. Positive parenting can buffer these risky pathways. © The Royal College of Psychiatrists 2016.

Heritability of targeted gene modifications induced by plant-optimized CRISPR systems.

PubMed

Mao, Yanfei; Botella, Jose Ramon; Zhu, Jian-Kang

2017-03-01

The Streptococcus-derived CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 (CRISPR-associated protein 9) system has emerged as a very powerful tool for targeted gene modifications in many living organisms including plants. Since the first application of this system for plant gene modification in 2013, this RNA-guided DNA endonuclease system has been extensively engineered to meet the requirements of functional genomics and crop trait improvement in a number of plant species. Given its short history, the emphasis of many studies has been the optimization of the technology to improve its reliability and efficiency to generate heritable gene modifications in plants. Here we review and analyze the features of customized CRISPR/Cas9 systems developed for plant genetic studies and crop breeding. We focus on two essential aspects: the heritability of gene modifications induced by CRISPR/Cas9 and the factors affecting its efficiency, and we provide strategies for future design of systems with improved activity and heritability in plants.

Heritable temperament pathways to early callous–unemotional behaviour

PubMed Central

Waller, Rebecca; Trentacosta, Christopher J.; Shaw, Daniel S.; Neiderhiser, Jenae M.; Ganiban, Jody M.; Reiss, David; Leve, Leslie D.; Hyde, Luke W.

2016-01-01

Background Early callous–unemotional behaviours identify children at risk for antisocial behaviour. Recent work suggests that the high heritability of callous–unemotional behaviours is qualified by interactions with positive parenting. Aims To examine whether heritable temperament dimensions of fearlessness and low affiliative behaviour are associated with early callous–unemotional behaviours and whether parenting moderates these associations. Method Using an adoption sample (n = 561), we examined pathways from biological mother self-reported fearlessness and affiliative behaviour to child callous–unemotional behaviours via observed child fearlessness and affiliative behaviour, and whether adoptive parent observed positive parenting moderated pathways. Results Biological mother fearlessness predicted child callous–unemotional behaviours via earlier child fearlessness. Biological mother low affiliative behaviour predicted child callous–unemotional behaviours, although not via child affiliative behaviours. Adoptive mother positive parenting moderated the fearlessness to callous–unemotional behaviour pathway. Conclusions Heritable fearlessness and low interpersonal affiliation traits contribute to the development of callous–unemotional behaviours. Positive parenting can buffer these risky pathways. PMID:27765772

Link Prediction in Criminal Networks: A Tool for Criminal Intelligence Analysis

PubMed Central

Berlusconi, Giulia; Calderoni, Francesco; Parolini, Nicola; Verani, Marco; Piccardi, Carlo

2016-01-01

The problem of link prediction has recently received increasing attention from scholars in network science. In social network analysis, one of its aims is to recover missing links, namely connections among actors which are likely to exist but have not been reported because data are incomplete or subject to various types of uncertainty. In the field of criminal investigations, problems of incomplete information are encountered almost by definition, given the obvious anti-detection strategies set up by criminals and the limited investigative resources. In this paper, we work on a specific dataset obtained from a real investigation, and we propose a strategy to identify missing links in a criminal network on the basis of the topological analysis of the links classified as marginal, i.e. removed during the investigation procedure. The main assumption is that missing links should have opposite features with respect to marginal ones. Measures of node similarity turn out to provide the best characterization in this sense. The inspection of the judicial source documents confirms that the predicted links, in most instances, do relate actors with large likelihood of co-participation in illicit activities. PMID:27104948

Getting patients in the door: medical appointment reminder preferences

PubMed Central

Crutchfield, Trisha M; Kistler, Christine E

2017-01-01

Purpose Between 23% and 34% of outpatient appointments are missed annually. Patients who frequently miss medical appointments have poorer health outcomes and are less likely to use preventive health care services. Missed appointments result in unnecessary costs and organizational inefficiencies. Appointment reminders may help reduce missed appointments; particular types may be more effective than other types. We used a survey with a discrete choice experiment (DCE) to learn why individuals miss appointments and to assess appointment reminder preferences. Methods We enrolled a national sample of adults from an online survey panel to complete demographic and appointment habit questions as well as a 16-task DCE designed in Sawtooth Software’s Discover tool. We assessed preferences for four reminder attributes – initial reminder type, arrival of initial reminder, reminder content, and number of reminders. We derived utilities and importance scores. Results We surveyed 251 adults nationally, with a mean age of 43 (range 18–83) years: 51% female, 84% White, and 8% African American. Twenty-three percent of individuals missed one or more appointments in the past 12 months. Two primary reasons given for missing an appointment include transportation problems (28%) and forgetfulness (26%). Participants indicated the initial reminder type (21%) was the most important attribute, followed by the number of reminders (10%). Overall, individuals indicated a preference for a single reminder, arriving via email, phone call, or text message, delivered less than 2 weeks prior to an appointment. Preferences for reminder content were less clear. Conclusion The number of missed appointments and reasons for missing appointments are consistent with prior research. Patient-centered appointment reminders may improve appointment attendance by addressing some of the reasons individuals report missing appointments and by meeting patients’ needs. Future research is necessary to determine if preferred reminders used in practice will result in improved appointment attendance in clinical settings. PMID:28182131

Multiple imputation to deal with missing EQ-5D-3L data: Should we impute individual domains or the actual index?

PubMed

Simons, Claire L; Rivero-Arias, Oliver; Yu, Ly-Mee; Simon, Judit

2015-04-01

Missing data are a well-known and widely documented problem in cost-effectiveness analyses alongside clinical trials using individual patient-level data. Current methodological research recommends multiple imputation (MI) to deal with missing health outcome data, but there is little guidance on whether MI for multi-attribute questionnaires, such as the EQ-5D-3L, should be carried out at domain or at summary score level. In this paper, we evaluated the impact of imputing individual domains versus imputing index values to deal with missing EQ-5D-3L data using a simulation study and developed recommendations for future practice. We simulated missing data in a patient-level dataset with complete EQ-5D-3L data at one point in time from a large multinational clinical trial (n = 1,814). Different proportions of missing data were generated using a missing at random (MAR) mechanism and three different scenarios were studied. The performance of using each method was evaluated using root mean squared error and mean absolute error of the actual versus predicted EQ-5D-3L indices. In large sample sizes (n > 500) and a missing data pattern that follows mainly unit non-response, imputing domains or the index produced similar results. However, domain imputation became more accurate than index imputation with pattern of missingness following an item non-response. For smaller sample sizes (n < 100), index imputation was more accurate. When MI models were misspecified, both domain and index imputations were inaccurate for any proportion of missing data. The decision between imputing the domains or the EQ-5D-3L index scores depends on the observed missing data pattern and the sample size available for analysis. Analysts conducting this type of exercises should also evaluate the sensitivity of the analysis to the MAR assumption and whether the imputation model is correctly specified.