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Background The fertility of a chicken's egg is a trait which depends on both the hen that lays the egg and on her mate. It is also known that fertility of an individual changes over the laying period. Methods Longitudinal models including both random genetic and permanent environmental effects of both the female and her male mate were used to model the proportion of fertile eggs in a pedigree broiler population over the ages 29-54 weeks. Results Both the male and the female contribute to variation in fertility. Estimates of heritability of weekly records were typically 7% for female and 10% for male contributions to fertility. Repeatability estimates ranged from 24 to 33%, respectively. The estimated genetic variance remained almost constant for both sexes over the laying period and the genetic correlations between different ages were close to 1.0. The permanent environment components increased substantially towards the end of the analyzed period, and correlations between permanent environment effects at different ages declined with increasing age difference The heritability of mean fertility over the whole laying period was estimated at 13% for females and 17% for males. A small positive correlation between genetic effects for male and female fertility was found. Conclusion Opportunities to improve fertility in broiler stocks by selection on both sexes exist and should have an impact throughout the laying period.

Background Here, we jointly summarise scientific evidence for genetic variation in resistance to infection with Mycobacterium bovis , the primary agent of bovine tuberculosis ( TB ), provided by two recent and separate studies of Holstein-Friesian dairy cow populations in Great Britain ( GB ) and Ireland. Methods The studies quantified genetic variation within archived data from field and abattoir surveillance control programmes within each country. These data included results from the single intradermal comparative tuberculin test ( SICTT ), abattoir inspection for TB lesions and laboratory confirmation of disease status. Threshold animal models were used to estimate variance components for responsiveness to the SICTT and abattoir confirmed M. bovis infection. The link functions between the observed 0/1 scale and the liability scale were the complementary log-log in the GB, and logit link function in the Irish population. Results and discussion The estimated heritability of susceptibility to TB, as judged by responsiveness to the SICTT, was 0.16 (0.012) and 0.14 (0.025) in the GB and Irish populations, respectively. For abattoir or laboratory confirmation of infection, estimates were 0.18 (0.044) and 0.18 (0.041) from the GB and the Irish populations, respectively. Conclusions Estimates were all significantly different from zero and indicate that exploitable variation exists among GB and Irish Holstein Friesian dairy cows for resistance to TB. Epidemiological analysis suggests that factors such as variation in exposure or imperfect sensitivity and specificity would have resulted in underestimation of the true values.

Aims were to estimate the extent of genetic heterogeneity in environmental variance. Data comprised 99 535 records of 35-day body weights from broiler chickens reared in a controlled environment. Residual variance within dam families was estimated using ASREML, after fitting fixed effects such as genetic groups and hatches, for each of 377 genetically contemporary sires with a large number of progeny (> 100 males or females each). Residual variance was computed separately for male and female offspring, and after correction for sampling, strong evidence for heterogeneity was found, the standard deviation between sires in within variance amounting to 15–18% of its mean. Reanalysis using log-transformed data gave similar results, and elimination of 2–3% of outlier data reduced the heterogeneity but it was still over 10%. The correlation between estimates for males and females was low, however. The correlation between sire effects on progeny mean and residual variance for body weight was small and negative (-0.1). Using a data set bigger than any yet presented and on a trait measurable in both sexes, this study has shown evidence for heterogeneity in the residual variance, which could not be explained by segregation of major genes unless very few determined the trait.

Farrowing survival is usually analysed as a trait of the sow, but this precludes estimation of any direct genetic effects associated with individual piglets. In order to estimate these effects, which are particularly important for sire lines, it is necessary to fit an animal model. However this can be computationally very demanding. We show how direct and maternal genetic effects can be estimated with a simpler analysis based on the reduced animal model and we illustrate the method using farrowing survival information on 118 193 piglets in 10 314 litters. We achieve a 30% reduction in computing time and a 70% reduction in memory use, with no important loss of accuracy. This use of the reduced animal model is not only of interest for pig breeding but also for poultry and fish breeding where large full-sib families are performance tested.

Model selection is an essential issue in longitudinal data analysis since many different models have been proposed to fit the covariance structure. The likelihood criterion is commonly used and allows to compare the fit of alternative models. Its value does not reflect, however, the potential improvement that can still be reached in fitting the data unless a reference model with the actual covariance structure is available. The score test approach does not require the knowledge of a reference model, and the score statistic has a meaningful interpretation in itself as a goodness-of-fit measure. The aim of this paper was to show how the score statistic may be separated into the genetic and environmental parts, which is difficult with the likelihood criterion, and how it can be used to check parametric assumptions made on variance and correlation parameters. Selection of models for genetic analysis was applied to a dairy cattle example for milk production.

Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55–85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9–11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (–1%, 95% CI –15 to 12, for progression-free survival; 0%, –10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. UK Medical Research Council and Prostate Cancer UK.

Chromosome deletions in the mouse have proven invaluable in the dissection of gene function. The brown deletion complex comprises >28 independent genome rearrangements, which have been used to identify several functional loci on chromosome 4 required for normal embryonic and postnatal development. We have constructed a 172-bacterial artificial chromosome contig that spans this 22-megabase (Mb) interval and have produced a contiguous, finished, and manually annotated sequence from these clones. The deletion complex is strikingly gene-poor, containing only 52 protein-coding genes (of which only 39 are supported by human homologues) and has several further notable genomic features, including several segments of <1 Mb, apparently devoid of a coding sequence. We have used sequence polymorphisms to finely map the deletion breakpoints and identify strong candidate genes for the known phenotypes that map to this region, including three lethal loci (I4Rnl, I4Rn2, and I4Rn3) and the fitness mutant brown-associated fitness (baf). We have also characterized misexpression of the basonuclin homologue, Bnc2, associated with the inversion-mediated coat color mutant white-based brown ($B^{w}$). This study provides a molecular insight into the basis of several characterized mouse mutants, which will allow further dissection of this region by targeted or chemical mutagenesis.