Optimizing Randomized Trial Designs to Distinguish which Subpopulations Benefit from Treatment

It is a challenge to evaluate experimental treatments where it is suspected that the treatment effect may only be strong for certain subpopulations, such as those having a high initial severity of disease, or those having a particular gene variant. Standard randomized controlled trials can have low power in such situations. They also are not optimized to distinguish which subpopulations benefit from a treatment. With the goal of overcoming these limitations, we consider randomized trial designs in which the criteria for patient enrollment may be changed, in a preplanned manner, based on interim analyses. Since such designs allow data-dependent changes to the population sampled, care must be taken to ensure strong control of the familywise Type I error rate. Our main contribution is a general method for constructing randomized trial designs that (1) allow changes (based on a prespecified decision rule) to the population enrolled based on interim data, (2) make no parametric model assumptions, and (3) guarantee the asymptotic, familywise Type I error rate is strongly controlled at a specified level. As a demonstration of our method, we prove new, sharp results for a simple, two-stage enrichment design. We then compare this design to a fixed design, focusing on each design\u27s ability to determine overall and subpopulation specific treatment effects

Using Regression Models to Analyze Randomized Trials: Asymptotically Valid Hypothesis Tests Despite Incorrectly Specified Models

Regression models are often used to test for cause-effect relationships from data collected in randomized trials or experiments. This practice has deservedly come under heavy scrutiny, since commonly used models such as linear and logistic regression will often not capture the actual relationships between variables, and incorrectly specified models potentially lead to incorrect conclusions. In this paper, we focus on hypothesis test of whether the treatment given in a randomized trial has any effect on the mean of the primary outcome, within strata of baseline variables such as age, sex, and health status. Our primary concern is ensuring that such hypothesis tests have correct Type I error for large samples. Our main result is that for a surprisingly large class of commonly used regression models, standard regression-based hypothesis tests (but using robust variance estimators) are guaranteed to have correct Type I error for large samples, even when the models are incorrectly specified. To the best of our knowledge, this robustness of such model-based hypothesis tests to incorrectly specified models was previously unknown for Poisson regression models and for other commonly used models we consider. Our results have practical implications for understanding the reliability of commonly used, model-based tests for analyzing randomized trials

Simple Examples of Estimating Causal Effects Using Targeted Maximum Likelihood Estimation

We present a brief overview of targeted maximum likelihood for estimating the causal effect of a single time point treatment and of a two time point treatment. We focus on simple examples demonstrating how to apply the methodology developed in (van der Laan and Rubin, 2006; Moore and van der Laan, 2007; van der Laan, 2010a,b). We include R code for the single time point case

Allelopathic interference potential of the alien invader plant Parthenium hysterophorus

The alien invader plant Parthenium hysterophorus is a Category 1 weed in South Africa, where it poses a serious threat to indigenous vegetation in particular, and to biodiversity in general. In addition to its competitive ability, it is hypothesized that the successful invasiveness of P. hysterophorus is linked to the allelopathic potential of the plant. One compound in particular, parthenin, is alleged to play a major role in this allelopathic potential. Interference between P. hysterophorus and three indigenous grass species (Eragrostis curvula, Panicum maximum, Digitaria eriantha) was investigated on a site with a natural parthenium infestation at Skukuza, Kruger National Park. The trial was conducted over two growing seasons on exclosure plots which eliminated mammal herbivory. P. maximum displayed best overall performance and was eventually able to completely overwhelm P. hysterophorus. Eragrostis curvula and D. eriantha grew more favourably in the second season after becoming better established but were clearly not well adapted to the trial conditions. Although P. maximum was the supreme interferer, all grasses were able to significantly interfere with P. hysterophorus growth in the second season. The ability of P. maximum to interfere with P. hysterophorus growth so efficiently that it caused mortalities of the latter species, indicates that P. maximum exhibits high potential for use as an antagonistic species in an integrated control programme. An investigation on the production dynamics of parthenin in the leaves of P. hysterophorus indicated that high levels of this compound are produced and maintained in the plant up until senescence. The high resource allocation priority of the plant towards this secondary metabolite even in the final growth stages may indicate the use of residual allelopathy to inhibit or impede the recruitment of other species. Studies on the persistence of parthenin in soil revealed that parthenin is readily degraded in soil and that microbial degradation appears to play a predominant role. Significant differences between parthenin disappearance-time half-life (DT50) values were observed in soils incubated at different temperatures and in soils with different textures. Exposure of the three grass species to pure parthenin showed that, in terms of their early development, the order of sensitivity of the grasses was: Panicum maximum>Digitaria eriantha>Eragrostis curvula. It may therefore prove challenging to establish P. maximum from seed in P. hysterophorus stands during the execution of an integrated control programme due to the sensitivity of this grass species to parthenin. From the research findings it appears possible that P. hysterophorus can inhibit or impede the recruitment of indigenous vegetation under natural conditions. At least one mechanism through which this alien species can exert its negative influence on other plant species is the production and release of parthenin.Dissertation (MSc (Agric) Agronomy)--University of Pretoria, 2007.Plant Production and Soil Scienceunrestricte

Development, testing and application of a crop nitrogen and phosphorus model to investigate leaching losses at the local scale

The leaching of nitrogen (N) and phosphorus (P) from the rootzone of cropping systems is a major contributor of non-point source pollution resulting in deterioration of fresh water supplies. An escalating world population is forcing further intensification of agricultural production practices and the identification of suitable and effective management practices to reduce N and P leaching losses is becoming ever more important. Such leaching losses are, however, extremely challenging to measure and quantify due to uncertainties associated with the estimation of deep drainage and N and P concentrations in this drainage water. SWB-Sci is a locally developed, mechanistic crop model to which N and P subroutines have been added to enable analysis of leaching losses at the local scale. This involved novel approaches to estimate the effects of N deficiencies on yield; to simulate crop P demand, uptake and stress effects; to simulate banded P fertilizer applications; and to estimate incomplete solute mixing. New equations to estimate the size of the Labile P pool from soil P tests commonly used in South Africa, and guidelines on the classification of South African soils as calcareous, slightly weathered or highly weathered which is required to simulate P, were also developed. The upgraded more versatile model was tested using historical datasets from the Netherlands, Kenya and South Africa, and performed well in simulating N and P dynamics in maize and wheat cropping systems. Variables tested included aboveground dry matter production, yield, leaf area index, aboveground crop N and P mass, grain N and P mass, soil water content ABSTRACT xvii and soil inorganic N levels. A study was also conducted on a large drainage lysimeter into which suction cups and wetting front detectors were installed, and data from this experiment together with the SWB-Sci model was used to study vertical solute movement more closely. As hypothesized, wetting front detector nitrate (NO3-) and P concentrations were observed to align closely with simulated mobile phase concentrations, and suction cup NO3- concentrations were observed to align closely with simulated immobile phase concentrations. These results confirm that monitoring and modelling can be used together to improve understanding and obtain more accurate estimates of N and P leaching losses, and further work on this approach is recommended for a wide range of soils and cropping systems. Finally, long-term modelling with the SWB-Sci model was used to analyse and compare N and P leaching losses from a dryland versus an irrigated monoculture maize production system. Over a 30 year simulation period, irrigated maize was estimated to leach considerably higher loads of N and P (~ 4-fold higher). For dryland production, zero leaching was observed for consecutive years on several occasions, with major leaching losses associated with high rainfall events. A ‘room for rain’ irrigation scheduling management practice was estimated to reduce N leaching by 12% and P leaching by 14%, while a crop rotation system which incorporated wheat grown over the winter months was estimated to reduce N leaching by 23% and P leaching by 24%. From this study, long-term modelling was confirmed as an effective approach to investigate N and P leaching losses, to assist with the planning and design of field trials, and to assess the effectiveness of best management practices. It is envisaged that SWB-Sci will continue to evolve as a valuable tool for analysing and reducing N and P leaching losses from cropping systems to further reduce non-point source pollution.Thesis (PhD)--University of Pretoria, 2010.Plant Production and Soil Scienceunrestricte

Identification of Regulatory Elements Using A Feature Selection Method

Many methods have been described to identify regulatory motifs in the transcription control regions of genes that exhibit similar patterns of gene expression across a variety of experimental conditions. Here we focus on a single experimental condition, and utilize gene expression data to identify sequence motifs associated with genes that are activated under this experimental condition. We use a linear model with two way interactions to model gene expression as a function of sequence features (words) present in presumptive transcription control regions. The most relevant features are selected by a feature selection method called stepwise selection with monte carlo cross validation. We apply this method to a publicly available dataset of the yeast Saccharomyces cerevisiae, focussing on the 800 basepairs immediately upstream of each gene\u27s translation start site (the upstream control region (UCR)). We successfully identify regulatory motifs that are known to be active under the experimental conditions analyzed, and find additional significant sequences that may represent novel regulatory motifs. We also discuss a complementary method that utilizes gene expression data from a single microarray experiment and allows averaging over variety of experimental conditions as an alternative to motif finding methods that act on clusters of co-expressed genes

Interactions between irrigated agriculture and surface water quality with a focus on phosphate and nitrate in the Middle Olifants Catchment, South Africa

Little is understood on the interaction between irrigated agriculture and surface water quality in South African catchments. A case study was conducted on the Middle Olifants Catchment, which contains the second largest irrigation scheme in South Africa. Dams, rivers, irrigation canals, and drainage canals were sampled between the Loskop and Flag Boshielo Dams. Results were compared to historical water quality monitoring data from the Department of Water and Sanitation (DWS). While DWS data indicate that phosphate-phosphorus (PO4-P) does not pose a eutrophication risk, our monitored data were above the eutrophication threshold for the majority of the sampling period. In general, phosphorus (P) pollution is a bigger issue than nitrogen (N), and concentrations of these nutrients tend to be higher during the summer rainfall months, potentially indicating a link to agriculture and fertilization events. We estimated that waste water treatment works (WWTW), which are currently systematically failing in South Africa, have the potential to pollute as much P as irrigated agriculture. Electrical conductivity levels increased downstream, moving from the acceptable towards the tolerable category, while the sodium adsorption ratio (SAR) presents a moderate risk of infiltrability problems. The pH values were generally in the ideal range. This study has highlighted existing and looming water quality issues for irrigation and the environment in the Middle Olifants. Similar scoping studies are recommended for other intensively-irrigated catchments in the region to identify issues and allow timely intervention.This research was funded by the Water Research Commission (Project title “Quantifying and Managing Agricultural Nitrogen and Phosphorus Pollution from Field to Catchment Scale”) grant number K5/2510//4 and report number TT 792/19. The APC was funded by the University of Pretoria.http://www.mdpi.com/journal/sustainabilityam2021Plant Production and Soil Scienc

The Value of Information in Reverse Logistics

We explore the value of information in the context of a remanufacturer that faces uncertainty with respect to demand, product return, and product recovery (yield loss). We assume a single period model in which the operational decision of interest is the quantity of new product to order. Our objective is to evaluate the absolute and relative value of the different types of information that such a firm may choose to invest in order to reduce the uncertainty it experiences in matching supply with demand. The different types of information include demand, return, and yield loss. Our results are extensive and reveal that the value for any specific type of information depends both on the overall level of uncertainty and the level of uncertainty that is attributed to the information for which it explains. We develop and test a theoretical model that is predictive of 1) the value of each type of information, 2) the conditions that give rise to the value for each type of information, and 3) the relative value for each type of information

Detailed Version: Analyzing Direct Effects in Randomized Trials with Secondary Interventions: An Application to HIV Prevention Trials

This is the detailed technical report that accompanies the paper “Analyzing Direct Effects in Randomized Trials with Secondary Interventions: An Application to HIV Prevention Trials” (an unpublished, technical report version of which is available online at http://www.bepress.com/ucbbiostat/paper223). The version here gives full details of the models for the time-dependent analysis, and presents further results in the data analysis section. The Methods for Improving Reproductive Health in Africa (MIRA) trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing HIV infection among susceptible women. 5,045 women were randomly assigned to either the active treatment arm or not. Additionally, all subjects in both arms received intensive condom counselling and provision, the gold standard HIV prevention barrier method. There was much lower reported condom use in the intervention arm than in the control arm, making it difficult to answer important public health questions based solely on the intention-to-treat analysis. We adapt an analysis technique from causal inference to estimate the direct effects of assignment to the diaphragm arm, adjusting for condom use in an appropriate sense. Issues raised in the MIRA trial apply to other trials of HIV prevention methods, some of which are currently being conducted or designed