Haseman-Elston weighted by marker informativity

In the Haseman-Elston approach the squared phenotypic difference is regressed on the proportion of alleles shared identical by descent (IBD) to map a quantitative trait to a genetic marker. In applications the IBD distribution is estimated and usually cannot be determined uniquely owing to incomplete marker information. At Genetic Analysis Workshop (GAW) 13, Jacobs et al. [BMC Genet 2003, 4(Suppl 1):S82] proposed to improve the power of the Haseman-Elston algorithm by weighting for information available from marker genotypes. The authors did not show, however, the validity of the employed asymptotic distribution. In this paper, we use the simulated data provided for GAW 14 and show that weighting Haseman-Elston by marker information results in increased type I error rates. Specifically, we demonstrate that the number of significant findings throughout the chromosome is significantly increased with weighting schemes. Furthermore, we show that the classical Haseman-Elston method keeps its nominal significance level when applied to the same data. We therefore recommend to use Haseman-Elston with marker informativity weights only in conjunction with empirical p-values. Whether this approach in fact yields an increase in power needs to be investigated further

Genome-Wide Linkage Analysis of Malaria Infection Intensity and Mild Disease

Although balancing selection with the sickle-cell trait and other red blood cell disorders has emphasized the interaction between malaria and human genetics, no systematic approach has so far been undertaken towards a comprehensive search for human genome variants influencing malaria. By screening 2,551 families in rural Ghana, West Africa, 108 nuclear families were identified who were exposed to hyperendemic malaria transmission and were homozygous wild-type for the established malaria resistance factors of hemoglobin (Hb)S, HbC, alpha(+) thalassemia, and glucose-6-phosphate-dehydrogenase deficiency. Of these families, 392 siblings aged 0.5–11 y were characterized for malaria susceptibility by closely monitoring parasite counts, malaria fever episodes, and anemia over 8 mo. An autosome-wide linkage analysis based on 10,000 single-nucleotide polymorphisms was conducted in 68 selected families including 241 siblings forming 330 sib pairs. Several regions were identified which showed evidence for linkage to the parasitological and clinical phenotypes studied, among them a prominent signal on Chromosome 10p15 obtained with malaria fever episodes (asymptotic z score = 4.37, empirical p-value = 4.0 × 10(−5), locus-specific heritability of 37.7%; 95% confidence interval, 15.7%–59.7%). The identification of genetic variants underlying the linkage signals may reveal as yet unrecognized pathways influencing human resistance to malaria

OECD validation study to assess intra- and inter-laboratory reproducibility of the zebrafish embryo toxicity test for acute aquatic toxicity testing

The OECD validation study of the zebrafish embryo acute toxicity test (ZFET) for acute aquatic toxicity testing evaluated the ZFET reproducibility by testing 20 chemicals at 5 different concentrations in 3 independent runs in at least 3 laboratories. Stock solutions and test concentrations were analytically confirmed for 11 chemicals. Newly fertilised zebrafish eggs (20/concentration and control) were exposed for 96 h to chemicals. Four apical endpoints were recorded daily as indicators of acute lethality: coagulation of the embryo, lack of somite formation, non-detachment of the tail bud from the yolk sac and lack of heartbeat. Results (LC50 values for 48/96 h exposure) show that the ZFET is a robust method with a good intra- and inter-laboratory reproducibility (CV 30%) for some very toxic or volatile chemicals, and chemicals tested close to their limit of solubility. The ZFET is now available as OECD Test Guideline 236. Considering the high predictive capacity of the ZFET demonstrated by Belanger et al. (2013) in their retrospective analysis of acute fish toxicity and fish embryo acute toxicity data, the ZFET is ready to be considered for acute fish toxicity for regulatory purposes

SIBSIM - quantitative phenotype simulation in extended pedigreesFranke

A tool (SIBSIM) is described for quantitative phenotype simulation in extended pedigrees. Download and installation information are given and the advantages and limitations of the tool are described. The input format is based on XML and the different sections of an input file are explained. A short explanation of the algorithm is given. Links to the download site, the user manual, and related literature as well as a detailed example are included.Availability: The software is available at: http://www.imbs.uni-luebeck.de/pub/sibsi