Comparison of four statistical methods for detection of a major gene in a progeny test design

In livestock improvement it is common to design a progeny test of sires in order to estimate their breeding values. The data recorded for these estimate are useful for the detection of major genes. They are the n.m performances Yij of m progeny j of n sires i. These data need to be corrected for the polygenic influence of the sire on its progeny (sire i effect Ui). Four statistical tests of the segregation of a major gene are compared. The first (ﺎSA for "segregation analysis") is the classical ratio of the likelihoods under Ho (no major gene) and H1 (a major gene is segregating). The parameters describing the population (means and standard deviations within genotype) are estimated by maximizing the marginal likelihood of the Yij. The other statistics studied are approximations of this ﺎSA statistic where the sire i effect (Ui) is considered as a fixed effect (ﺎ FE statistic) or, following Elsen et al. (1988) and Höschele (1988), where the parameters, and Ui, are estimated maximizing the joint likelihood of Ui and Yij (ﺎME and ﺎME2 statistics). Simulation studies were done in order to describe the distribution of these statistics. It is shown that ﺎSA and ﺎME1 are the most powerful test, followed by ﺎME2 whose relative loss of power ranged between 20 and 40%, depending on the H1 case studied, when 400 progeny are measured (n = m = 20). The segregation analysis, based on direct maximization of the likelihood, required 30 times more computation time than the ﺎME test using an EM algorithm.Il est fréquent, en sélection, de tester sur descendance, des mâles, afin d’estimer leur valeur génétique. Les données recueillies dans ce but peuvent être utilisées afin de mettre en évidence un gène majeur. Elles sont constituées des n.m performances Yij de m descendants j de n mâles i. Ces données doivent être corrigées pour l’effet polygénique du père (Ui) sur ses descendants. Quatre tests statistiques de mise en évidence d’un tel gène majeur sont comparés. Le premier (ﺎSA pour "segregation analysis") est le rapport classique des vraisemblances sous Ho (pas de gène majeur) et sous H1 (existence d’un gène majeur). Les paramètres caractéristiques de la population (moyennes et écarts types intragénotype) sont estimés en maximisant la vraisemblance marginale des Yij Les autres statistiques de tests sont des approximations de ﺎSA pour lesquelles, soit l’effet père Ui est considéré comme un effet fixé (test IFE) soit, comme proposé par Elsen et al. (1988) et Höschele (1988), les paramètres, et Ui, sont obtenus en maximisant la vraisemblance conjointe des Yij et des Ui (test ﺎME1 et ﺎME2 Nous avons réalisé des simulations afin de décrire les distributions de ces tests. ﺎSA et ﺎME1 sont les tests les plus puissants, suivi par ﺎME2 dont la perte relative de puissance varie entre 20 et 40% selon l’hypothèse H1 étudiées, quand 400 descendants sont mesurés (n = m =20). L’analyse de ségrégation, réalisée par maximisation directe de la vraisemblance, demande 30 fois plus de temps de calcul que les tests ﺎME réalisés l’aide d’un algorithme EM

In search for the role of thermospermine synthase gene in poplar vascular development

This work is supported by the FCT project PTDC/AGR-GPL/098369/2008 and FCT PhD grant SFRH/BD/30074/2006 (A.M.).Peer Reviewe

A fast algorithm for estimating transmission probabilities in QTL detection designs with dense maps

<p>Abstract</p> <p>Background</p> <p>In the case of an autosomal locus, four transmission events from the parents to progeny are possible, specified by the grand parental origin of the alleles inherited by this individual. Computing the probabilities of these transmission events is essential to perform QTL detection methods.</p> <p>Results</p> <p>A fast algorithm for the estimation of these probabilities conditional to parental phases has been developed. It is adapted to classical QTL detection designs applied to outbred populations, in particular to designs composed of half and/or full sib families. It assumes the absence of interference.</p> <p>Conclusion</p> <p>The theory is fully developed and an example is given.</p

Guidelines for the recording and evaluation of pharmaco-EEG data in man: the International Pharmaco-EEG Society (IPEG)

The International Pharmaco-EEG Society (IPEG) presents updated guidelines summarising the requirements for the recording and computerised evaluation of pharmaco-EEG data in man. Since the publication of the first pharmaco-EEG guidelines in 1982, technical and data processing methods have advanced steadily, thus enhancing data quality and expanding the palette of tools available to investigate the action of drugs on the central nervous system (CNS), determine the pharmacokinetic and pharmacodynamic properties of novel therapeutics and evaluate the CNS penetration or toxicity of compounds. However, a review of the literature reveals inconsistent operating procedures from one study to another. While this fact does not invalidate results per se, the lack of standardisation constitutes a regrettable shortcoming, especially in the context of drug development programmes. Moreover, this shortcoming hampers reliable comparisons between outcomes of studies from different laboratories and hence also prevents pooling of data which is a requirement for sufficiently powering the validation of novel analytical algorithms and EEG-based biomarkers. The present updated guidelines reflect the consensus of a global panel of EEG experts and are intended to assist investigators using pharmaco-EEG in clinical research, by providing clear and concise recommendations and thereby enabling standardisation of methodology and facilitating comparability of data across laboratories

Quantitative cardiovascular magnetic resonance myocardial perfusion mapping to assess hyperaemic response to adenosine stress

AIMS: Assessment of hyperaemia during adenosine stress cardiovascular magnetic resonance (CMR) remains a clinical challenge with lack of a gold-standard non-invasive clinical marker to confirm hyperaemic response. This study aimed to validate maximum stress myocardial blood flow (SMBF) measured using quantitative perfusion mapping for assessment of hyperaemic response and compare this to current clinical markers of adenosine stress. METHODS AND RESULTS: Two hundred and eighteen subjects underwent adenosine stress CMR. A derivation cohort (22 volunteers) was used to identify a SMBF threshold value for hyperaemia. This was tested in a validation cohort (37 patients with suspected coronary artery disease) who underwent invasive coronary physiology assessment on the same day as CMR. A clinical cohort (159 patients) was used to compare SMBF to other physiological markers of hyperaemia [splenic switch-off (SSO), heart rate response (HRR), and blood pressure (BP) fall]. A minimum SMBF threshold of 1.43 mL/g/min was derived from volunteer scans. All patients in the coronary physiology cohort demonstrated regional maximum SMBF (SMBFmax) >1.43 mL/g/min and invasive evidence of hyperaemia. Of the clinical cohort, 93% had hyperaemia defined by perfusion mapping compared to 71% using SSO and 81% using HRR. There was no difference in SMBFmax in those with or without SSO (2.58 ± 0.89 vs. 2.54 ± 1.04 mL/g/min, P = 0.84) but those with HRR had significantly higher SMBFmax (2.66 1.86 mL/g/min, P 15 bpm was superior to SSO in predicting adequate increase in SMBF (AUC 0.87 vs. 0.62, P < 0.001). CONCLUSION: Adenosine-induced increase in myocardial blood flow is accurate for confirmation of hyperaemia during stress CMR studies and is superior to traditional, clinically used markers of adequate stress such as SSO and BP response

Genetic variation in the pleiotropic association between physical activity and body weight in mice

<p>Abstract</p> <p>Background</p> <p>A sedentary lifestyle is often assumed to lead to increases in body weight and potentially obesity and related diseases but in fact little is known about the genetic association between physical activity and body weight. We tested for such an association between body weight and the distance, duration, and speed voluntarily run by 310 mice from the F₂generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels.</p> <p>Methods</p> <p>We used a conventional interval mapping approach with SNP markers to search for QTLs that affected both body weight and activity traits. We also conducted a genome scan to search for relationship QTLs (<it>rel</it>QTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight.</p> <p>Results</p> <p>We uncovered seven quantitative trait loci (QTLs) affecting body weight, but only one co-localized with another QTL previously found for activity traits. We discovered 19 <it>rel</it>QTLs that provided evidence for a genetic (pleiotropic) association of physical activity and body weight. The three genotypes at each of these loci typically exhibited a combination of negative, zero, and positive regressions of the activity traits on body weight, the net effect of which was to produce overall independence of body weight from physical activity. We also demonstrated that the <it>rel</it>QTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome.</p> <p>Conclusion</p> <p>It was concluded that individuals with specific combinations of genotypes at the <it>rel</it>QTLs and <it>epi</it>QTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight.</p

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p

The Effects of Dietary Carotenoid Supplementation and Retinal Carotenoid Accumulation on Vision-Mediated Foraging in the House Finch

BACKGROUND: For many bird species, vision is the primary sensory modality used to locate and assess food items. The health and spectral sensitivities of the avian visual system are influenced by diet-derived carotenoid pigments that accumulate in the retina. Among wild House Finches (Carpodacus mexicanus), we have found that retinal carotenoid accumulation varies significantly among individuals and is related to dietary carotenoid intake. If diet-induced changes in retinal carotenoid accumulation alter spectral sensitivity, then they have the potential to affect visually mediated foraging performance. METHODOLOGY/PRINCIPAL FINDINGS: In two experiments, we measured foraging performance of house finches with dietarily manipulated retinal carotenoid levels. We tested each bird's ability to extract visually contrasting food items from a matrix of inedible distracters under high-contrast (full) and dimmer low-contrast (red-filtered) lighting conditions. In experiment one, zeaxanthin-supplemented birds had significantly increased retinal carotenoid levels, but declined in foraging performance in the high-contrast condition relative to astaxanthin-supplemented birds that showed no change in retinal carotenoid accumulation. In experiments one and two combined, we found that retinal carotenoid concentrations predicted relative foraging performance in the low- vs. high-contrast light conditions in a curvilinear pattern. Performance was positively correlated with retinal carotenoid accumulation among birds with low to medium levels of accumulation (∼0.5-1.5 µg/retina), but declined among birds with very high levels (>2.0 µg/retina). CONCLUSION/SIGNIFICANCE: Our results suggest that carotenoid-mediated spectral filtering enhances color discrimination, but that this improvement is traded off against a reduction in sensitivity that can compromise visual discrimination. Thus, retinal carotenoid levels may be optimized to meet the visual demands of specific behavioral tasks and light environments

A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper

<p>Abstract</p> <p>Background</p> <p>Given the growing population of cardiac surgery patients with impaired preoperative cardiac function and rapidly expanding surgical techniques, continued efforts to improve myocardial protection strategies are warranted. Prior research is mostly limited to either large animal models or <it>ex vivo </it>preparations. We developed a new <it>in vivo </it>survival model that combines administration of antegrade cardioplegia with endoaortic crossclamping during cardiopulmonary bypass (CPB) in the rat.</p> <p>Methods</p> <p>Sprague-Dawley rats were cannulated for CPB (n = 10). With ultrasound guidance, a 3.5 mm balloon angioplasty catheter was positioned via the right common carotid artery with its tip proximal to the aortic valve. To initiate cardioplegic arrest, the balloon was inflated and cardioplegia solution injected. After 30 min of cardioplegic arrest, the balloon was deflated, ventilation resumed, and rats were weaned from CPB and recovered. To rule out any evidence of cerebral ischemia due to right carotid artery ligation, animals were neurologically tested on postoperative day 14, and their brains histologically assessed.</p> <p>Results</p> <p>Thirty minutes of cardioplegic arrest was successfully established in all animals. Functional assessment revealed no neurologic deficits, and histology demonstrated no gross neuronal damage.</p> <p>Conclusion</p> <p>This novel small animal CPB model with cardioplegic arrest allows for both the study of myocardial ischemia-reperfusion injury as well as new cardioprotective strategies. Major advantages of this model include its overall feasibility and cost effectiveness. In future experiments long-term echocardiographic outcomes as well as enzymatic, genetic, and histologic characterization of myocardial injury can be assessed. In the field of myocardial protection, rodent models will be an important avenue of research.</p