Sequential methods for pharmacogenetic studies

A study or experiment can be described as sequential if its design includes one or more interim analyses at which it is possible to stop the study, having reached a definitive conclusion concerning the primary question of interest. The potential of the sequential study to terminate earlier than the equivalent fixed sample size study means that, typically, there are ethical and economic advantages to be gained from using a sequential design. These advantages have secured a place for the methodology in the conduct of many clinical trials of novel therapies. Recently, there has been increasing interest in pharmacogenetics: the study of how DNA variation in the human genome affects the safety and efficacy of drugs. The potential for using sequential methodology in pharmacogenetic studies is considered and the conduct of candidate gene association studies, family-based designs and genome-wide association studies within the sequential setting is explored. The objective is to provide a unified framework for the conduct of these types of studies as sequential designs and hence allow experimenters to consider using sequential methodology in their future pharmacogenetic studies.

A sequential two meal challenge reveals abnormalities in postprandial TAG but not glucose in men with increasing numbers of metabolic syndrome components

Objective To examine the impact of increasing numbers of metabolic syndrome (MetS) components on postprandial lipaemia. Methods Healthy men (n = 112) underwent a sequential meal postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (0 min) and lunch (330 min). Lipids and glucose were measured in the fasting sample, with triacylglycerol (TAG), non-esterified fatty acids and glucose analysed in the postprandial samples. Results Subjects were grouped according to the number of MetS components regardless of the combinations of components (0/1, 2, 3 and 4/5). As expected, there was a trend for an increase in body mass index, blood pressure, fasting TAG, glucose and insulin, and a decrease in fasting high-density lipoprotein cholesterol with increasing numbers of MetS components (P≤0.0004). A similar trend was observed for the summary measures of the postprandial TAG and glucose responses. For TAG, the area under the curve (AUC) and maximum concentration (maxC) were significantly greater in men with ≥ 3 than < 3 components (P < 0.001), whereas incremental AUC was greater in those with 3 than 0/1 and 2, and 4/5 compared with 2 components (P < 0.04). For glucose, maxC after the test breakfast (0-330 min) and total AUC (0-480 min) were higher in men with ≥ 3 than < 3 components (P≤0.001). Conclusions Our data analysis has revealed a linear trend between increasing numbers of MetS components and magnitude (AUC) of the postprandial TAG and glucose responses. Furthermore, the two meal challenge discriminated a worsening of postprandial lipaemic control in subjects with ≥ 3 MetS components.

Production and processing asymmetries in the acquisition of tense morphology by sequential bilingual children

This study investigates the production and on-line processing of English tense morphemes by sequential bilingual (L2) Turkish-speaking children with more than three years of exposure to English. Thirty nine 6-9-year-old L2 children and 28 typically developing age-matched monolingual (L1) children were administered the production component for third person –s and past tense of the Test for Early Grammatical Impairment (Rice & Wexler, 1996) and participated in an on-line word-monitoring task involving grammatical and ungrammatical sentences with presence/omission of tense (third person –s, past tense -ed) and non-tense (progressive –ing, possessive ‘s) morphemes. The L2 children’s performance on the on-line task was compared to that of children with Specific Language Impairment (SLI) in Montgomery & Leonard (1998, 2006) to ascertain similarities and differences between the two populations. Results showed that the L2 children were sensitive to the ungrammaticality induced by the omission of tense morphemes, despite variable production. This reinforces the claim about intact underlying syntactic representations in child L2 acquisition despite non target-like production (Haznedar & Schwartz, 1997).

Advances in sequential data assimilation and numerical weather forecasting: an Ensemble Transform Kalman-Bucy Filter, a study on clustering in deterministic Ensemble Square Root Filters, and a test of a new time stepping scheme in an atmospheric model

This dissertation deals with aspects of sequential data assimilation (in particular ensemble Kalman filtering) and numerical weather forecasting. In the first part, the recently formulated Ensemble Kalman-Bucy (EnKBF) filter is revisited. It is shown that the previously used numerical integration scheme fails when the magnitude of the background error covariance grows beyond that of the observational error covariance in the forecast window. Therefore, we present a suitable integration scheme that handles the stiffening of the differential equations involved and doesn’t represent further computational expense. Moreover, a transform-based alternative to the EnKBF is developed: under this scheme, the operations are performed in the ensemble space instead of in the state space. Advantages of this formulation are explained. For the first time, the EnKBF is implemented in an atmospheric model. The second part of this work deals with ensemble clustering, a phenomenon that arises when performing data assimilation using of deterministic ensemble square root filters in highly nonlinear forecast models. Namely, an M-member ensemble detaches into an outlier and a cluster of M-1 members. Previous works may suggest that this issue represents a failure of EnSRFs; this work dispels that notion. It is shown that ensemble clustering can be reverted also due to nonlinear processes, in particular the alternation between nonlinear expansion and compression of the ensemble for different regions of the attractor. Some EnSRFs that use random rotations have been developed to overcome this issue; these formulations are analyzed and their advantages and disadvantages with respect to common EnSRFs are discussed. The third and last part contains the implementation of the Robert-Asselin-Williams (RAW) filter in an atmospheric model. The RAW filter is an improvement to the widely popular Robert-Asselin filter that successfully suppresses spurious computational waves while avoiding any distortion in the mean value of the function. Using statistical significance tests both at the local and field level, it is shown that the climatology of the SPEEDY model is not modified by the changed time stepping scheme; hence, no retuning of the parameterizations is required. It is found the accuracy of the medium-term forecasts is increased by using the RAW filter.

Fine-root turnover rates of European forests revisited: an analysis of data from sequential coring and ingrowth cores

Background and Aims Forest trees directly contribute to carbon cycling in forest soils through the turnover of their fine roots. In this study we aimed to calculate root turnover rates of common European forest tree species and to compare them with most frequently published values. Methods We compiled available European data and applied various turnover rate calculation methods to the resulting database. We used Decision Matrix and Maximum-Minimum formula as suggested in the literature. Results Mean turnover rates obtained by the combination of sequential coring and Decision Matrix were 0.86 yr−1 for Fagus sylvatica and 0.88 yr−1 for Picea abies when maximum biomass data were used for the calculation, and 1.11 yr−1 for both species when mean biomass data were used. Using mean biomass rather than maximum resulted in about 30 % higher values of root turnover. Using the Decision Matrix to calculate turnover rate doubled the rates when compared to the Maximum-Minimum formula. The Decision Matrix, however, makes use of more input information than the Maximum-Minimum formula. Conclusions We propose that calculations using the Decision Matrix with mean biomass give the most reliable estimates of root turnover rates in European forests and should preferentially be used in models and C reporting.

Parsing the passive: comparing children with Specific Language Impairment to sequential bilingual children

25 monolingual (L1) children with Specific Language Impairment (SLI), 32 sequential bilingual (L2) children, and 29 L1 controls completed the Test of Active & Passive Sentences-Revised (van der Lely, 1996) and the self-paced listening task with picture verification for actives and passives (Marinis, 2007). These revealed important between-group differences in both tasks. The children with SLI showed difficulties in both actives and passives when they had to reanalyse thematic roles on-line. Their error pattern provided evidence for working memory limitations. The L2 children showed difficulties only in passives both on-line and off-line. We suggest that these relate to the complex syntactic algorithm in passives and reflect an earlier developmental stage due to reduced exposure to the L2. The results are discussed in relation to theories of SLI and can be best accommodated within accounts proposing that difficulties in the comprehension of passives stem from processing limitations.

Janus PEG-based dendrimers for use in combination therapy: controlled multi-drug loading and sequential release

The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different “model drugs”, benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15–0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.

Scheduling satellite-based SAR acquisition for sequential assimilation of water level observations into flood modelling

Satellite-based Synthetic Aperture Radar (SAR) has proved useful for obtaining information on flood extent, which, when intersected with a Digital Elevation Model (DEM) of the floodplain, provides water level observations that can be assimilated into a hydrodynamic model to decrease forecast uncertainty. With an increasing number of operational satellites with SAR capability, information on the relationship between satellite first visit and revisit times and forecast performance is required to optimise the operational scheduling of satellite imagery. By using an Ensemble Transform Kalman Filter (ETKF) and a synthetic analysis with the 2D hydrodynamic model LISFLOOD-FP based on a real flooding case affecting an urban area (summer 2007,Tewkesbury, Southwest UK), we evaluate the sensitivity of the forecast performance to visit parameters. We emulate a generic hydrologic-hydrodynamic modelling cascade by imposing a bias and spatiotemporal correlations to the inflow error ensemble into the hydrodynamic domain. First, in agreement with previous research, estimation and correction for this bias leads to a clear improvement in keeping the forecast on track. Second, imagery obtained early in the flood is shown to have a large influence on forecast statistics. Revisit interval is most influential for early observations. The results are promising for the future of remote sensing-based water level observations for real-time flood forecasting in complex scenarios.

A sequential procedure for comparing two experimental treatments with a control

A procedure is described in which patients are randomized between two experimental treatments and a control. At a series of interim analyses, each experimental treatment is compared with control. One of the experimental treatments might then be found sufficiently superior to the control for it to be declared the best treatment, and the trial stopped. Alternatively, experimental treatments might be eliminated from further consideration at any stage. It is shown how the procedure can be conducted while controlling overall error probabilities. Data concerning evaluation of different doses of riluzole in the treatment of motor neurone disease are used for illustration.

Sequential variations of phytoplankton growth and mortality in an NPZ model: a remote-sensing-based assessment

Radiometric data in the visible domain acquired by satellite remote sensing have proven to be powerful for monitoring the states of the ocean, both physical and biological. With the help of these data it is possible to understand certain variations in biological responses of marine phytoplankton on ecological time scales. Here, we implement a sequential data-assimilation technique to estimate from a conventional nutrient–phytoplankton–zooplankton (NPZ) model the time variations of observed and unobserved variables. In addition, we estimate the time evolution of two biological parameters, namely, the specific growth rate and specific mortality of phytoplankton. Our study demonstrates that: (i) the series of time-varying estimates of specific growth rate obtained by sequential data assimilation improves the fitting of the NPZ model to the satellite-derived time series: the model trajectories are closer to the observations than those obtained by implementing static values of the parameter; (ii) the estimates of unobserved variables, i.e., nutrient and zooplankton, obtained from an NPZ model by implementation of a pre-defined parameter evolution can be different from those obtained on applying the sequences of parameters estimated by assimilation; and (iii) the maximum estimated specific growth rate of phytoplankton in the study area is more sensitive to the sea-surface temperature than would be predicted by temperature-dependent functions reported previously. The overall results of the study are potentially useful for enhancing our understanding of the biological response of phytoplankton in a changing environment.

Production and on-line comprehension of definite articles and clitic pronouns by Greek sequential bilingual children and monolingual children with specific language impairment

The present study compared production and on-line comprehension of definite articles and third person direct object clitic pronouns in Greek-speaking typically developing, sequential bilingual (L2-TD) children and monolingual children with specific language impairment (L1-SLI). Twenty Turkish Greek L2-TD children, 16 Greek L1-SLI children, and 31 L1-TD Greek children participated in a production task examining definite articles and clitic pronouns and, in an on-line comprehension task, involving grammatical sentences with definite articles and clitics and sentences with grammatical violations induced by omitted articles and clitics. The results showed that the L2-TD children were sensitive to the grammatical violations despite low production. In contrast, the children with SLI were not sensitive to clitic omission in the on-line task, despite high production. These results support a dissociation between production and on-line comprehension in L2 children and for impaired grammatical representations and lack of automaticity in children with SLI. They also suggest that on-line comprehension tasks may complement production tasks by differentiating between the language profiles of L2-TD children and children with SLI.