SURFBAT: a surrogate family-based association test building on large imputation reference panels.

Genotype-phenotype association tests are typically adjusted for population stratification using principal components that are estimated genome-wide. This lacks resolution when analysing populations with fine structure and/or individuals with fine levels of admixture. This can affect power and precision, and is a particularly relevant consideration when control individuals are recruited using geographic selection criteria.

Ravages: An R package for the simulation and analysis of rare variants in multicategory phenotypes.

Current software packages for the analysis and the simulations of rare variants are only available for binary and continuous traits. Ravages provides solutions in a single R package to perform rare variant association tests for multicategory, binary and continuous phenotypes, to simulate datasets under different scenarios and to compute statistical power. Association tests can be run in the whole genome thanks to C++ implementation of most of the functions, using either RAVA-FIRST, a recently developed strategy to filter and analyse genome-wide rare variants, or user-defined candidate regions.

Testing for association with rare variants in the coding and non-coding genome: RAVA-FIRST, a new approach based on CADD deleteriousness score.

Rare variant association tests (RVAT) have been developed to study the contribution of rare variants widely accessible through high-throughput sequencing technologies. RVAT require to aggregate rare variants in testing units and to filter variants to retain only the most likely causal ones. In the exome, genes are natural testing units and variants are usually filtered based on their functional consequences.

Moment estimators of relatedness from low-depth whole-genome sequencing data.

Background: Estimating relatedness is an important step for many genetic study designs. A variety of methods for estimating coefficients of pairwise relatedness from genotype data have been proposed. Both the kinship coefficient [Formula: see text] and the fraternity coefficient [Formula: see text] for all pairs of individuals are of interest.

Do children with mathematical learning disabilities use the inversion principle to solve three-term arithmetic problems?: The impact of presentation mode.

Numerical inversion is the ability to understand that addition is the opposite of subtraction and vice versa. Three-term arithmetic problems can be solved without calculation using this conceptual shortcut. To verify that this principle is used, inverse problems (a + b - b) can be compared with standard problems (a + b - c).

DNA damage in circulating leukocytes measured with the comet assay may predict the risk of death.

The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan-Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p < 0.

The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders.

The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge.

Collection and storage of human white blood cells for analysis of DNA damage and repair activity using the comet assay in molecular epidemiology studies.

DNA damage and repair activity are often assessed in blood samples from humans in different types of molecular epidemiology studies. However, it is not always feasible to analyse the samples on the day of collection without any type of storage. For instance, certain studies use repeated sampling of cells from the same subject or samples from different subjects collected at different time-points, and it is desirable to analyse all these samples in the same comet assay experiment.

Extension of SKAT to multi-category phenotypes through a geometrical interpretation.

Rare genetic variants are expected to play an important role in disease and several statistical methods have been developed to test for disease association with rare variants, including variance-component tests. These tests however deal only with binary or continuous phenotypes and it is not possible to take advantage of a suspected heterogeneity between subgroups of patients. To address this issue, we extended the popular rare-variant association test SKAT to compare more than two groups of individuals.

Mixed logistic regression in genome-wide association studies.

Background: Mixed linear models (MLM) have been widely used to account for population structure in case-control genome-wide association studies, the status being analyzed as a quantitative phenotype. Chen et al. proved in 2016 that this method is inappropriate in some situations and proposed GMMAT, a score test for the mixed logistic regression (MLR).

The Time Knowledge Questionnaire for children.

Based on a definition of time knowledge as the correct representation and use of the various time units, a validated questionnaire, the Time Knowledge Questionnaire (TKQ) has been developed with norms for typically developing children aged 6-11 years. The TKQ is a relatively short (10-45 min) and innovative tool, comprising 25 questions broken down into 7 categories. The TKQ has good internal consistency.

Rare variant association testing for multicategory phenotype.

Genetic association studies have provided new insights into the genetic variability of human complex traits with a focus mainly on continuous or binary traits. Methods have been proposed to take into account disease heterogeneity between subgroups of patients when studying common variants but none was specifically designed for rare variants. Because rare variants are expected to have stronger effects and to be more heterogeneously distributed among cases than common ones, subgroup analyses might be particularly attractive in this context.

Detecting the dominance component of heritability in isolated and outbred human populations.

Inconsistencies between published estimates of dominance heritability between studies of human genetic isolates and human outbred populations incite investigation into whether such differences result from particular trait architectures or specific population structures. We analyse simulated datasets, characteristic of genetic isolates and of unrelated individuals, before analysing the isolate of Cilento for various commonly studied traits. We show the strengths of using genetic relationship matrices for variance decomposition over identity-by-descent based methods in a population isolate and that heritability estimates in isolates will avoid the downward biases that may occur in studies of samples of unrelated individuals; irrespective of the simulated distribution of causal variants.

Validation of Gelbond® high-throughput alkaline and Fpg-modified comet assay using a linear mixed model.

Even if the comet assay has been widely used for decades, there is still a need for controlled studies and good mathematical models to assess the variability of the different versions of this assay and in particular to assess potential intra-experimental variability of the high-throughput comet assay. To address this point, we further validate a high-throughput comet assay that uses hydrophilic polyester film (Gelbond®). Experiments were performed using human peripheral blood mononuclear cells (PBMC) either untreated or treated with different concentration of MMS (methyl methanesulfonate).

Accuracy of heritability estimations in presence of hidden population stratification.

The heritability of a trait is the proportion of its variance explained by genetic factors; it has historically been estimated using familial data. However, new methods have appeared for estimating heritabilities using genomewide data from unrelated individuals. A drawback of this strategy is that population stratification can bias the estimates.

TNFSF10/TRAIL regulates human T4 effector memory lymphocyte radiosensitivity and predicts radiation-induced acute and subacute dermatitis.

Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10)mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity.

Time knowledge acquisition in children aged 6 to 11 years and its relationship with numerical skills.

Acquisition of time knowledge (TK; the correct representation and use of time units) is linked to the development of numerical abilities, but this relationship has not been investigated in children. The current study examined the acquisition of TK and its association with numerical skills. A total of 105 children aged 6 to 11 years were interviewed with our Time Knowledge Questionnaire (TKQ), developed for purposes of this study, and the Zareki-R, a battery for the evaluation of number processing and mental calculation.

A Bagged, Partially Linear, Tree-Based Regression Procedure for Prediction and Variable Selection.

Objectives: In genomics, variable selection and prediction accounting for the complex interrelationships between explanatory variables represent major challenges. Tree-based methods are powerful alternatives to classical regression models. We have recently proposed the generalized, partially linear, tree-based regression (GPLTR) procedure that integrates the advantages of generalized linear regression (allowing the incorporation of confounding variables) and of tree-based models.

Where is the causal variant? On the advantage of the family design over the case-control design in genetic association studies.

Many associated single-nucleotide polymorphisms (SNPs) have been identified by association studies for numerous diseases. However, the association between a SNP and a disease can result from a causal variant in linkage disequilibrium (LD) with the considered SNP. Assuming that the true causal variant is among the genotyped SNPs, other authors demonstrated that the power to discriminate between it and other SNPs in LD is low.

The Use of the Linear Mixed Model in Human Genetics.

We give a short but detailed review of the methods used to deal with linear mixed models (restricted likelihood, AIREML algorithm, best linear unbiased predictors, etc.), with a few original points. Then we describe three common applications of the linear mixed model in contemporary human genetics: association testing (pathways analysis or rare variants association tests), genomic heritability estimates, and correction for population stratification in genome-wide association studies.

Inbreeding coefficient estimation with dense SNP data: comparison of strategies and application to HapMap III.

Background/aims: If the parents of an individual are related, it is possible for the individual to have received at 1 locus 2 identical-by-descent alleles that are copies of a single allele carried by the parents' common ancestor. The inbreeding coefficient measures the probability of this event and increases with increasing relatedness between the parents. It is traditionally computed from the observed inbreeding loops in the genealogies and its accuracy thus depends on the depth and reliability of the genealogies.