Solutions for surrogacy validation with longitudinal outcomes for a gene therapy

Valid surrogate endpoints S can be used as a substitute for a true outcome of interest T to measure treatment efficacy in a clinical trial. We propose a causal inference approach to validate a surrogate by incorporating longitudinal measurements of the true outcomes using a mixed modeling approach, and we define models and quantities for validation that may vary across the study period using principal surrogacy criteria. We consider a surrogate-dependent treatment efficacy curve that allows us to validate the surrogate at different time points. We extend these methods to accommodate a delayed-start treatment design where all patients eventually receive the treatment. Not all parameters are identified in the general setting. We apply a Bayesian approach for estimation and inference, utilizing more informative prior distributions for selected parameters. We consider the sensitivity of these prior assumptions as well as assumptions of independence among certain counterfactual quantities conditional on pretreatment covariates to improve identifiability. We examine the frequentist properties (bias of point and variance estimates, credible interval coverage) of a Bayesian imputation method. Our work is motivated by a clinical trial of a gene therapy where the functional outcomes are measured repeatedly throughout the trial.     

The energetic equivalence of cover to juvenile coho salmon (Oncorhynchus kisutch): ideal free distribution theroy applied

Cover is often thought to be an important habitat characteristicfor juvenile stream salmonida. In addition to providing protectionfrom predators, cover may be associated with reduced food availability.Thus, an individual's use of cover is likely to reflect a trade-offbetween the conflicting demands of growth and survival. We measuredthe influence of cover on foraging-site selection in groupsof eight juvenile coho salmon (Oncorhynchus kisutch) by examiningtheir distribution across two stream channel patches, one providingaccess to cover but little food (the "poor" patch), the otherproviding more food but no cover (the "good" patch). Becausefish distributions in the absence of cover conformed to an idealfree distribution (IFD) for unequal competitors (i.e., the distributionof competitive abilities matched the distribution of food),we used IFD theory to quantify the energetic equivalence ofcover to the fish. In the presence of cover and a model avianpredator, use of the poor patch increased relative to the predictionsof the IFD model. Using this observed deviation from an IFD,we calculated how much extra food must be added to the goodpatch to return the distribution of fish to the previously observedIFD of unequal competitors. As predicted, adding this amountof food caused the fish to return to their previous distribution,demonstrating that IFD theory can be used to relate energy intakeand risk of predation in a common currency     

Microsatellite tagging of the stripe-rust resistance gene YrH52 derived from wild emmer wheat, Triticum dicoccoides, and suggestive negative crossover interference on chromosome 1B

 Stripe rust caused by Puccinia striifomis West. is one of the most devastating diseases relating to wheat production. Wild emmer wheat, Triticum dicoccoides, the tetraploid progenitor of cultivated wheat, has proven to be a valuable source of novel stripe-rust resistance genes for wheat breeding. For example, T. dicoccoides accessions from Mt. Hermon, Israel, are uniformly and highly resistant to stripe-rust. The main objective of the present study is to map a stripe-rust resistance gene, derived from the unique Mt. Hermon population of wild emmer, using microsatellite markers. An F₂ mapping population was established by crossing stripe-rust resistant T. dicoccoides accession H52 from Mt. Hermon with the Triticum durum cultivar Langdon. The stripe-rust resistance derived from accession H52 was found to be controlled by a single dominant gene which was temporarily designated as YrH52. Out of 120 microsatellite markers tested, 109 (91%) showed polymorphism between the parental lines. Among 79 segregating microsatellite loci generated from 56 microsatellite primer pairs, nine were linked to YrH52 with recombination frequencies of 0.02–0.35, and LOD scores of 3.56–54.22. A genetic map of chromosome 1B, consisting of ten microsatellite loci and the stripe-rust resistance gene YrH52, was constructed with a total map length of 101.5 cM. YrH52 is also closely linked to RFLP marker Nor1 with a map distance of 1.4 cM and a LOD value of 29.62. Apparent negative crossover interference was observed in chromosome 1B, especially in the region spanning the centromere. Negative crossover interference may be a common characteristic of gene-rich regions or gene clusters in specific chromosomes. Received: 30 October 1998 / Accepted: 2 November 1998     

HEMIFLAGELLOCHLORIS KAZAKHSTANICA GEN. ET SP. NOV.: A NEW COCCOID GREEN ALGA WITH FLAGELLA OF CONSIDERABLY UNEQUAL LENGTHS FROM A SALINE IRRIGATION LAND IN KAZAKHSTAN (CHLOROPHYCEAE,CHLOROPHYTA)1

A coccoid green alga, Hemiflagellochloris kazakhstanica S. Watanabe, S. Tsujimura, T. Misono, S. Nakamura et H. Inoue, gen. et sp. nov., was described from soil samples of a saline irrigation land in Ili River basin, Kazakhstan. This alga had a parietal chloroplast with a pyrenoid, which was covered with starch segments and penetrated with thylakoid membranes. Reproduction occurred by the formation of aplanospores and zoospores. The aplanospores frequently formed tetrad aggregations in a mother cell. The zoospores were covered by a single‐layered cell wall and lacked stigmata. The zoospores had two flagella of considerably unequal lengths; the longer flagellum was 17–19 lm in length and the shorter one was 9–10 lm. The flagellar apparatus architecture was of the clockwise orientation group type in the Chlorophyceae. Molecular phylogenetic analysis using 18S and 28S rDNA sequence data resolved this organism in a separate clade from the green algae that had flagella of slightly unequal lengths. It was suggested that features such as inequality in flagellar lengths, parallel exsertion of basal bodies, and subapical position of the flagellar apparatus were sporadically evolved.     

NextGen sequencing reveals short double crossovers contribute disproportionately to genetic diversity in Toxoplasma gondii

Background

Toxoplasma gondii is a widespread protozoan parasite of animals that causes zoonotic disease in humans. Three clonal variants predominate in North America and Europe, while South American strains are genetically diverse, and undergo more frequent recombination. All three northern clonal variants share a monomorphic version of chromosome Ia (ChrIa), which is also found in unrelated, but successful southern lineages. Although this pattern could reflect a selective advantage, it might also arise from non-Mendelian segregation during meiosis. To understand the inheritance of ChrIa, we performed a genetic cross between the northern clonal type 2 ME49 strain and a divergent southern type 10 strain called VAND, which harbors a divergent ChrIa.

Results

NextGen sequencing of haploid F1 progeny was used to generate a genetic map revealing a low level of conventional recombination, with an unexpectedly high frequency of short, double crossovers. Notably, both the monomorphic and divergent versions of ChrIa were isolated with equal frequency. As well, ChrIa showed no evidence of being a sex chromosome, of harboring an inversion, or distorting patterns of segregation. Although VAND was unable to self fertilize in the cat, it underwent successful out-crossing with ME49 and hybrid survival was strongly associated with inheritance of ChrIII from ME49 and ChrIb from VAND.

Conclusions

Our findings suggest that the successful spread of the monomorphic ChrIa in the wild has not been driven by meiotic drive or related processes, but rather is due to a fitness advantage. As well, the high frequency of short double crossovers is expected to greatly increase genetic diversity among progeny from genetic crosses, thereby providing an unexpected and likely important source of diversity.

Electronic supplementary material

The online version of this article (doi:10.1186/1471-2164-15-1168) contains supplementary material, which is available to authorized users.     

Genetic interference: don't stand so close to me

Meiosis is a dynamic process during which chromosomes undergo condensation, pairing, crossing-over and disjunction. Stringent regulation of the distribution and quantity of meiotic crossovers is critical for proper chromosome segregation in many organisms. In humans, aberrant crossover placement and the failure to faithfully segregate meiotic chromosomes often results in severe genetic disorders such as Down syndrome and Edwards syndrome. In most sexually reproducing organisms, crossovers are more evenly spaced than would be expected from a random distribution. This phenomenon, termed interference, was first reported in the early 20(th) century by Drosophila geneticists and has been subsequently observed in a vast range of organisms from yeasts to humans. Yet, many questions regarding the behavior and mechanism of interference remain poorly understood. In this review, we examine results new and old, from a wide range of organisms, to begin to understand the progress and remaining challenges to understanding the fundamental unanswered questions regarding genetic interference.     

滨海盐碱地棉花成苗的原理与技术

成苗是滨海盐碱地植棉的难点,建立和完善成苗技术是盐碱地棉花丰产的关键.本文在回顾前人相关研究的基础上,依据我们在该领域的研究进展,总结评述了土壤根区盐分差异分布、提墒增温、建立膜下温室和采用抗盐种衣剂促进棉花成苗的效应与机制.在土壤耕层平均盐分含量不能减少的情况下,通过诱导盐分在根区的差异分布、适度提高土壤含水量和地温,改善至少部分根区的生态环境,可显著减轻盐害,是促进盐碱地棉花成苗的重要途径.轻度盐碱地平作覆盖、中度和重度盐碱地沟畦覆盖、无灌溉条件下的预覆膜栽培、热量不足地区的短季棉晚播,是促进滨海盐碱地棉花成苗和增产的可靠技术.以上成苗理论与技术为滨海盐碱地棉花一播全苗提供了保障.     

Power analysis for cluster randomized trials with continuous coprimary endpoints

Pragmatic trials evaluating health care interventions often adopt cluster randomization due to scientific or logistical considerations. Systematic reviews have shown that coprimary endpoints are not uncommon in pragmatic trials but are seldom recognized in sample size or power calculations. While methods for power analysis based on K ($K\ge 2$) binary coprimary endpoints are available for cluster randomized trials (CRTs), to our knowledge, methods for continuous coprimary endpoints are not yet available. Assuming a multivariate linear mixed model (MLMM) that accounts for multiple types of intraclass correlation coefficients among the observations in each cluster, we derive the closed-form joint distribution of K treatment effect estimators to facilitate sample size and power determination with different types of null hypotheses under equal cluster sizes. We characterize the relationship between the power of each test and different types of correlation parameters. We further relax the equal cluster size assumption and approximate the joint distribution of the K treatment effect estimators through the mean and coefficient of variation of cluster sizes. Our simulation studies with a finite number of clusters indicate that the predicted power by our method agrees well with the empirical power, when the parameters in the MLMM are estimated via the expectation-maximization algorithm. An application to a real CRT is presented to illustrate the proposed method.     

A Concise Formula to Compute General Orthogonal Contrast Coefficients

A proof is given of a general formula conjectured by ABT to calculate the values of orthogonal polynomials for the case of nonequidistant levels and unequal numbers of observations. Also, a general derivation of the contrast coefficients is given on the basis of the conditions of orthogonality only. The practicality of the formulae with regard to applications in analysis of variance and regression analysis is stressed.