Browsing by Subject "Metaanalyse"

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    Extensions and applications of generalized linear mixed models for network meta-analysis of randomized controlled trials
    (2022) Wiksten, Anna; Piepho, Hans-Peter
    Network meta-analyses of published clinical trials has received increased attention over the past years with some meta-analytic publications having had a big impact on the cost-benefit assessment of important drugs. Much of the research has been based on Bayesian analysis using so called base-line contrast model. The research in network meta-analysis methodology has in parts been isolated from other fields of mathematical statistics and is lacking an integrative framework clearly separating statistical models and assumptions, inferential principles, and computational algorithms. The very extensive past research on ANOVA and MANOVA of un- balanced designs, variance component models, generalised linear models with fixed and/or random effects, provides a wealth of useful approaches and insights. These models are especially common in agricultural statistics and this thesis extended the use of the general statistical methods mainly applied in agricultural statistics to applications of network meta-analysis of clinical trials. The methods were applied to four different research problems in separate manuscripts. The first manuscript was based on a simulated case (based on real example) where some of the trials provided individual patient data and some only aggregated data. The outcome type considered was continuous normally distributed data. This manuscript provides models for jointly model the individual patient data and aggregated data. It was also explored how much information is lost if data is aggregated and how to quantify the amount of lost information. The second manuscript was based a real life dataset with pain medications used in acute postoperative pain. The outcome of interest was binomial, whether a subject experienced pain relief or not. The dataset used for NMA included 261 trials with 52 different treatment and dose combinations, making it extraordinarily rich and large network. The third manuscript developed methods for a case of time-to-event-outcome extracted from published Kaplan-Meier curves of survival analyses. This re-generated individual patient data was then used to model and compare the Kaplan-Meier curves and hazards of different treatments. The fourth manuscript of the thesis was tackling the problem of between-trial variance estimation for a specific method of Hartung-Knapp in classical two-treatment meta-analysis. The main finding of the paper was that in some cases random effect meta-analysis using Hartung-Knapp method may yield shorter confidence intervals for combined treatment effect than fixed effect meta-analysis and therefore the recommendation is to always compare results from Hartung-Knapp method with fixed effect meta-analysis. This thesis explored and developed the use of generalized linear mixed models in a setting of network meta-analysis of randomized clinical trials. In practice the most popular analysis method in the field of network meta-analysis has been the baseline contrast model which is usually fitted in a Bayesian framework. The baseline contrast model and Bayesian estimation provides great flexibility, but also come with some unnecessary complications for certain types of analyses. This thesis showed how methods originally developed and extensively used in agricultural research can be used in other field providing efficient calculation, estimation, and inference. Some of the examples used in this thesis arose from analyses needed for real applications in drug development and were directly used in medical research.  
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    Fertilizer placement and the potential for its combination with bio-effectors to improve crop nutrient acquisition and yield
    (2016) Nkebiwe, Peteh Mehdi; Müller, Torsten
    Even when total nitrogen (N) and phosphorus (P) concentrations in most agricultural soils are high, the concentrations of plant-available N and P fractions are often inadequate for acceptable yield. In comparison to conventional fertilizer application by homogenous broadcast over the soil surface (with or without subsequent incorporation), fertilizer placement in defined soil areas/volumes close to seeds or crop roots is a more effective application method to enhance the plant-availability of applied fertilizers. Nevertheless, considerable root growth in subsurface nutrient patches or around concentrated fertilizer-depots (and/or improved nutrient influx rates in roots) is a prerequisite for improved uptake of placed nutrients. Furthermore, zones with intense rooting around placed fertilizer depots (“rhizosphere hotspots”) with high concentrations of organic nutrients released as root exudates may be favorable for the survival and establishment of inoculated plant-growth-promoting microorganisms (PGPMs), which mobilize nutrients in soil to favor plant growth. In the last three decades, several published field studies comparing fertilizer placement to fertilizer broadcast arrived at different and often conflicting results regarding their effects on yield and nutrient status of various crops. For this reason, the first task was to conduct a Meta-analysis on data in published peer-reviewed field studies on fertilizer placement that met a set of pre-defined criteria for inclusion. We investigated the relative effect of fertilizer placement for specific fertilizer formulations (e.g. NH4+ and CO(NH2)2 without or in combination with soluble P (HPO42-; H2PO4-); soluble K; solid or liquid manure) in a precise restricted area on surface or subsurface soil in comparison to fertilizer broadcast on yield, nutrient concentration and content in above-ground plant parts. We utilized data from a total of 40 field studies published between 1982 and 2015 (85% of studies published from 2000) that met our criteria. We used the method of “baseline contrasts” to compare different fertilizer placement treatments to fertilizer broadcast as a common control or baseline treatment. Results showed that overall, fertilizer placement led to +3.7% higher yields, +3.7% higher concentrations of nutrients in above-ground plant parts and +11.9% higher contents of nutrients also in above-ground plant parts than fertilizer broadcast application. Placement depth had a strong effect of the outcome of fertilizer placement because relative placement effects increased with increasing fertilizer placement depth. Composition of fertilizer formulations was also an important factor. High yields of fertilizer placement relative to fertilizer broadcast application were obtained for CO(NH2)2 in combination with soluble P (HPO42-; H2PO4-) (+27%) or NH4+ in combination with HPO42-; H2PO4- (+15%) (Nkebiwe et al., 2016 a: Field Crops Research 196: 389–401). The next aim was to investigate the effect of fertilizer placement in subsurface soil in combination with application of bio-effectors (BEs) (PGPMs and natural active substances such as humic acids and seaweed extracts) on root growth of crop plants, establishment of inoculated PGPM in the rhizosphere, grain and biomass production as well as plant nutrient status for maize (Zea mays L) and wheat (Triticum aestivum L) cultures. Through various pot and rhizobox experiments, we observed that placement of a subsurface concentrated NH4+-fertilizer depot stabilized with the nitrification inhibitor DMPP (3,4-di-methylpyrazolphosphate) induced dense rooting around the depot contributing to more efficient exploitation of the depot. For this, it was crucial the N persisted in the depot mainly as poorly mobile NH4+, in order to induce localized depot-zone root-growth as well as favorable chemical and biological changes in the rhizosphere to improve N and P uptake by crop plants. Through in vitro culture experiments on solid and liquid media, we could show that via acidification of the growth media, several selected microbial BEs were capable to solubilize sparingly soluble inorganic phosphates and also that these BEs showed considerable tolerance to high concentrations of NH4+ und DMPP. The latter indicated a potential for the BEs to colonize plant roots in NH4+-rich well rooted soil zones around a subsurface NH4+-fertilizer depot (Nkebiwe et al., 2016 c: Manuscript submitted). Through further pot experiments and four others experiments as Bachelor and Master theses conduction under my supervision, we observed that certain BEs that readily solubilized tri-calcium phosphates in vitro were able to mobilize rock phosphate (RP) applied in soil-based substrates when N was supplied as stabilized NH4++DMPP, thereby contributing to enhanced P uptake and growth of maize and wheat plants. The bacterial BE Pseudomonas sp. DSMZ 13134 and BE consortia products containing bacteria and fungi such as CombiFectorA were good candidates. BE-induced RP-solubilzation occurred mainly in substrates with low CaCO3 contents indicating low P sorption capacity for neutral and moderately alkaline soils. With CombiFectorA, maize P-acquisition from sewage sludge ash could be enhanced, thus increasing the efficiency of a sparingly soluble fertilizer based of recycled wastes. Possible explanations for the beneficial effects of best performing BEs to improve plant growth were enhanced solubility of sparingly soluble P fertilizers via acidification of the rhizosphere and release of nutrient-chelating substances as well as improvement of root growth for better spatial interception of nutrients (Nkebiwe et al., 2016 d: Manuscript in preparation). Alongside, more greenhouse and two field experiments (grain maize 2014 and maize silage 2015) were designed, planned, conducted and evaluated. A peer-reviewed paper from this work has already been published (Nkebiwe et al., 2016 b: Chemical and Biological Technologies in Agriculture 3:15). In the greenhouse and experiments, placement of a concentrated stabilized NH4+-fertilizer depot led to improved root and shoot growth, and increased shoot N and P contents. Through intense root growth of maize around the NH4+-depot, increased root-colonization by Pseudomonas sp. DSMZ 13134 close to seeds could be observed. In the field, many weeks after subsurface placement of the concentrated stabilized NH4+-depot, it could be shown that N considerably persisted in the depot-zone as NH4+, which strongly induced depot-zone root growth. Placement of the NH4+-depot led to +7.4 % increase in grain yield of maize (2014) and +5.8% increase in maize silage yield (2015) in comparison to fertilizer broadcast. Placement of Pseudomonas sp. DSMZ 13134 inoculum in the sowing row let to +7.1% increase in yield of maize silage (2015) in comparison to the non-inoculated control. In total, these results showed that precise placement of specific fertilizer formulations in combination with the application of selected PGPMs can lead to improved plant growth, improved N and P uptake with a potential to save resources.
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    Mapping of quantitative-trait loci (QTL) for adult-plant resistance to Septoria tritici in five wheat populations (Triticum aestivum L.)
    (2010) Risser, Peter; Miedaner, Thomas
    Septoria tritici blotch (STB), caused by Septoria tritici (teleomorph Mycosphaerella graminicola), is one of the most important diseases in wheat varieties worldwide, responsible for severe damage of the leaves causing yield losses between 30 and 40 %. Control of STB includes crop rotation, soil tillage, fungicide application, and cultivation of resistant varieties. Profit-making wheat growers are forced to apply narrow crop rotations under reduced tillage. Some fungicides including widely-used strobilurins are no longer effective due to mutations in the highly variable pathogen population of S. tritici. Therefore, resistance breeding using genetic mapping to identify quantitative-trait loci (QTL) associated with STB resistance provides a promising strategy for controlling the disease. The main goal of this study was to detect chromosomal regions for quantitative adult-plant resistance of winter wheat to STB. Besides this, we analyzed the genetic diversity of 24 European varieties after inoculation with four different isolates of S. tritici. Multienvironmental field trials inoculated with S. tritici were applied to test isolates and varieties and to phenotype mapping populations. In detail, the objectives were to (1) compare natural infection and inoculation, (2) evaluate genotypic variation of adult-plant resistance to STB in European varieties, (3) analyze genotype x environment (G x E) interaction, (4) evaluate and analyze phenotypic data including STB severity, heading date (HED), and plant height (PLH) of five mapping populations, (5) construct genetic linkage maps of these populations using AFLP, DArT, and SSR markers, (6) determine number, positions, and genetic effects of QTL for evaluated traits, and (7) reveal QTL regions for multiple-disease resistance within mapping populations using QTL meta-analysis. In all trials, inoculation with one to four preselected isolates was performed and STB severity was visually scored plotwise as percentage coverage of flag leaves with lesions bearing pycnidia. 24 winter wheat varieties were chosen with maximal differentiation in resistance to STB and evaluated across three years including nine environments. Five mapping populations, Florett/Biscay, Tuareg/Biscay, History/Rubens, Arina/Forno, and Solitär/Bussard, each comprising a cross of a resistant and a susceptible variety, with population sizes ranging from 81 to 316, were phenotyped across four to six environments. In parallel, 221 to 491 polymorphic genetic markers were assigned to linkage groups covering 1,314 to 3,305 cM of the genome. Based on these linkage maps, the number, positions, and genetic effects of QTL could be determined by composite interval mapping. Furthermore, raw data of different experiments evaluated for resistance to two other pathogens, Fusarium head blight and Stagnospora glume blotch, were used to reveal multiple-disease resistance QTL within Arina/Forno and History/Rubens populations by the software package PLABMQTL. Results of inoculated field trials coincided with not inoculated trials showing natural infection (r = 0.84 to 0.99, P < 0.01), thus inoculation method was accurate to evaluate STB severity in the field. Genotypic variation between 24 varieties ranged from 8 % (Solitär) to 63 % (Rubens) flag leaf area infected. In the analysis of variance, genotypic variance had highest impact followed by G x E interaction (P < 0.01). Therefore, environmental stability of varieties should be a major breeding goal. The varieties Solitär, History, and Florett were most stable, as revealed by a regression approach. In contrast, disease symptoms of Biscay ranged from 19 to 72 % within the three experimental years. Phenotypic data revealed significant (P < 0.01) genotypic differentiation for STB, HED, and PLH within all five mapping populations and between the parents. Entry-mean heritabilities (h²) ranged from 0.69 to 0.87 for STB, the only exception was Tuareg/Biscay (h² = 0.38). For HED (h² = 0.78 to 0.93) and PLH (h² = 0.92 to 0.98) heritabilities were high. All correlations between STB and HED (r = -0.18 to -0.33) as well as between STB and PLH (r = -0.13 to -0.45) were negative and moderate. The exception was History/Rubens which is segregating at the Rht-D1 locus showing considerably higher correlation between STB and PLH (r = -0.55, P < 0.01). The five mapping populations showed a wide and continuous distribution of mean STB severity averaged across three to six environments in field trials at adult-plant stage. In QTL analysis, one to nine, zero to nine, and four to eleven QTL were detected for STB, HED, and PLH, respectively, across five wheat populations using composite interval mapping. One to two major QTL for resistance to STB were detected consistently across environments in each population (QStb.lsa_fb-3B, QStb.lsa_fb-6D, QStb.lsa_tb-4B, QStb.lsa_tb-6B, QStb.lsa_hr-4D, QStb.lsa_hr-5B.1, QStb.lsa_af-3B, QStb.lsa_bs-7A) explaining more than 10 % of normalized adjusted phenotypic variance. Altogether, resistance QTL explained 14 to 55 % of adjusted phenotypic variance. Both parents contributed resistant alleles. Major QTL, however, were all from the resistant parent. QTL meta-analysis revealed each of four loci for multiple-disease resistance located on chromosomes 3B, 4B, 5B, and 6D in Arina/Forno, and on chromosomes 2B, 4D, 5B, and 7B in History/Rubens. The most effective meta QTL was on chromosome 4D in History/Rubens closely linked to Rht-D1. The resistance allele from History reduced disease severity by 9.8 % for STB and 6.3 % for FHB, thus explaining 47 % and 60 % of partial phenotypic variance. In general, European wheat varieties showed a wide range of genotypic variation for STB resistance useful for breeding. Although the influence of environment and G x E interaction was high, some resistant varieties which were stable across multiple environments were found (Solitär, History, Florett). Genomic regions associated with STB resistance were mapped across 13 out of 21 wheat chromosomes. Together with the continuous distribution of five segregating populations for flag leaf infection, it can be concluded that the adult-plant resistance to S. tritici was inherited quantitatively depending on several loci explaining part of phenotypic variance. QTL meta-analysis across three severe pathogens, including Fusarium head blight, Stagnospora glume blotch, and STB, within two populations revealed eight loci for multiple-disease resistance with closely linked markers applicable in resistance breeding. Combining detected major QTL as well as meta QTL in present breeding material by applying marker-assisted selection seems a promising approach to the breeding of varieties with improved resistance to Septoria tritici blotch, Fusarium head blight, and Stagnospora glume blotch.