Fitting models for the joint action of two drugs using SAS(R)

Combinations of drugs are increasingly being used for a wide variety of diseases and conditions. A pre-clinical study may allow the investigation of the response at a large number of dose combinations. In determining the response to a drug combination, interest may lie in seeking evidence of synergism, in which the joint action is greater than the actions of the individual drugs, or of antagonism, in which it is less. Two well-known response surface models representing no interaction are Loewe additivity and Bliss independence, and Loewe or Bliss synergism or antagonism is defined relative to these. We illustrate an approach to fitting these models for the case in which the marginal single drug dose-response relationships are represented by four-parameter logistic curves with common upper and lower limits, and where the response variable is normally distributed with a common variance about the dose-response curve. When the dose-response curves are not parallel, the relative potency of the two drugs varies according to the magnitude of the desired effect and the models for Loewe additivity and synergism/antagonism cannot be explicitly expressed. We present an iterative approach to fitting these models without the assumption of parallel dose-response curves. A goodness-of-fit test based on residuals is also described. Implementation using the SAS NLIN procedure is illustrated using data from a pre-clinical study. Copyright © 2007 John Wiley & Sons, Ltd.

Joint effects of density and a growth inhibitor on the life history and population growth rate of the midge Chironomus riparius

Results of previous laboratory studies suggest that high population density often buffers the effects of chemical stressors that predominately increase mortality. Mortality stressors act to release more resources for the survivors and, therefore, produce less-than-additive effects. By contrast, growth stressors are expected to have opposite results or more-than-additive effects. We investigated the effects of a growth inhibitor (lufenuron) on larval growth and survival of Chironomus riparius and examined its joint effects with density on population growth rate (PGR). Exposure to 60 mu g/kg sediment or greater inhibited larval growth, and exposure to 88 mu g/kg or greater often resulted in mortality before reaching emergence. The effects of lufenuron, however, differed with population density. At 88 mu g/kg, mortalities and, to a lesser extent, reduced fecundity resulted in a reduction in PGR at low density. Conversely, when populations were initiated at high density, PGR was similar to that of controls, because the few survivors reached maturity sooner and started producing offspring earlier. The effect of density as a growth stressor therefore was stronger than the effect of lufenuron, which had effects similar to those of a mortality stressor and produced less-than-additive effects. Longterm studies under field conditions, however, are needed before less-than-additive effects are considered to be the norm.

Joint effects of population density and toxicant exposure on population dynamics of Capitella sp I

Very few studies have analyzed the dependence of population growth rate on population density, and even fewer have considered interaction effects of density and other stresses, such as exposure to toxic chemicals. Yet without such studies we cannot know whether chemicals harmful at low density have effects on carrying capacity or, conversely, whether chemicals reducing carrying capacity are also harmful at low density, impeding a population's capacity to recover from disturbance. This study examines the combined effects of population density and a toxicant (fluoranthene) on population growth rate (pgr) and carrying capacity using the deposit-feeding polychaete Capitella sp. I as a test organism. Populations were initiated with a stable age distribution, and population density and age/size distribution were followed during a period of 28 wk. Fluoranthene (FLU), population density, and their interaction influenced population growth rate. Population growth rate declined linearly with the logarithm of population biomass, but the slope of the relationship was steeper for the control populations than for populations exposed to 50 mug FLU/(g sediment dry mass). Populations exposed to 150 mug FLU/(g sediment dry mass) went extinct after 8 wk of exposure. Despite concerns that toxicant effects would be exacerbated at high density, we found the reverse to be the case, and effects of fluoranthene on population growth rate were much reduced in the region of carrying capacity. Fluoranthene did. reduce carrying capacity by 46%, and this could haven important implications for interacting species and/or sediment biogeochemical processes.

The joint effects of larval density and C-14-cypermethrin on the life history and population growth rate of the midge Chironomus riparius

1. Chemical effects on organisms are typically assessed using individual-level endpoints or sometimes population growth rate (PGR), but such measurements are generally made at low population densities. In contrast most natural populations are subject to density dependence and fluctuate around the environmental carrying capacity as a result of individual competition for resources. As ecotoxicology aims to make reliable population projections of chemical impacts in the field, an understanding of how high-density or resource-limited populations respond to environmental chemicals is essential. 2. Our objective was to determine the joint effects of population density and chemical stress on the life history and PGR of an important ecotoxicological indicator species, Chironomus riparius, under controlled laboratory conditions. Populations were fed the same ration but initiated at different densities and exposed to a solvent control and three concentrations of C-14-cypermethrin in a sediment-water test system for 67 days at 20 +/- 1 degreesC. 3. Density had a negative effect on all the measured life-history traits, and PGR declined with increasing density in the controls. Exposure to C-14-cypermethrin had a direct negative effect on juvenile survival, presumably within the first 24 h because the chemical rapidly dissipated from the water column. Reductions in the initial larval densities resulted in an increase in the available resources for the survivors. Subsequently, exposed populations emerged sooner and started producing offspring earlier than the controls. C-14-cypermethrin had no effect on estimated fecundity and adult body weight but interacted with density to reduce the time to first emergence and first reproduction. As a result, PGR increased with cypermethrin concentration when populations were initiated at high densities. 4. Synthesis and applications. The results showed that the effects of C-14-cypermethrin were buffered at high density, so that the joint effects of density and chemical stress on PGR were less than additive. Low levels of chemical stressors may increase carrying capacity by reducing juvenile competition for resources. More and perhaps fitter adults may be produced, similar to the effects of predators and culling; however, toxicant exposure may result in survivors that are less tolerant to changing conditions. If less than additive effects are typical in the field, standard regulatory tests carried out at low density may overestimate the effects of environmental chemicals. Further studies over a wide range of chemical stressors and organisms with contrasting life histories are needed to make general recommendations.

Joint importance of multistate systems

Importance measures in reliability engineering are used to identify weak areas of a system and signify the roles of components in either causing or contributing to proper functioning of the system. Traditional importance measures for multistate systems mainly concern reliability importance of an individual component and seldom consider the utility performance of the systems. This paper extends the joint importance concepts of two components from the binary system case to the multistate system case. A joint structural importance and a joint reliability importance are defined on the basis of the performance utility of the system. The joint structural importance measures the relationship of two components when the reliabilities of components are not available. The joint reliability importance is inferred when the reliabilities of the components are given. The properties of the importance measures are also investigated. A case study for an offshore electrical power generation system is given.

Accurate molecular structures of chlorothiazide and hydrochlorothiazide by joint refinement against powder neutron and X-ray diffraction data

The compounds chlorothiazide and hydrochlorothiazide (crystalline form II) have been studied in their fully hydrogenous forms by powder neutron diffraction on the GEM diffractometer. The results of joint Rietveld refinement of the structures against multi-bank neutron and single-bank X-ray powder data are reported and show that accurate and precise structural information can be obtained from polycrystalline molecular organic materials by this route.

Attention disengagement in children with developmental coordination disorder

Purpose. Previous research has shown that children with Developmental Coordination Disorder (DCD) have poorly developed strategies for allocating attention. This study examines the allocation of attention and integration of visuo-spatial and motor systems in children with DCD in a motor (look+hit condition) and a motor-free (look condition) task. Method. Three groups of control children were used to compare the performance of a group of children with DCD. Children were seated in front of a central fixation point and six peripheral targets, and were asked to look at or hit targets when illuminated. Saccade/hand movement latencies were measured on gap trials (gap between fixation offset and target onset) and overlap trials (fixation offset and target onset overlapped). Results. DCD children were not slower than controls to disengage attention during the look condition. However, during the look+hit condition the DCD children showed a prolonged disengagement period, which was also seen in younger control children. Conclusions. The results suggest that DCD children may have deficits in the allocation of attention for action, in both the speed of onset of a movement and the accuracy of the movement. It is concluded that attention disengagement may contribute to problems of visuo-motor integration in DCD.

Effects of divided attention and speeded responding on implicit and explicit retrieval of artificial grammar knowledge

The artificial grammar (AG) learning literature (see, e.g., Mathews et al., 1989; Reber, 1967) has relied heavily on a single measure of implicitly acquired knowledge. Recent work comparing this measure (string classification) with a more indirect measure in which participants make liking ratings of novel stimuli (e.g., Manza & Bornstein, 1995; Newell & Bright, 2001) has shown that string classification (which we argue can be thought of as an explicit, rather than an implicit, measure of memory) gives rise to more explicit knowledge of the grammatical structure in learning strings and is more resilient to changes in surface features and processing between encoding and retrieval. We report data from two experiments that extend these findings. In Experiment 1, we showed that a divided attention manipulation (at retrieval) interfered with explicit retrieval of AG knowledge but did not interfere with implicit retrieval. In Experiment 2, we showed that forcing participants to respond within a very tight deadline resulted in the same asymmetric interference pattern between the tasks. In both experiments, we also showed that the type of information being retrieved influenced whether interference was observed. The results are discussed in terms of the relatively automatic nature of implicit retrieval and also with respect to the differences between analytic and nonanalytic processing (Whittlesea Price, 2001).

Divided attention, selective attention and drawing: processing preferences in Williams syndrome are dependent on the task administered

The visuo-spatial abilities of individuals with Williams syndrome (WS) have consistently been shown to be generally weak. These poor visuo-spatial abilities have been ascribed to a local processing bias by some [R. Rossen, E.S. Klima, U. Bellugi, A. Bihrle, W. Jones, Interaction between language and cognition: evidence from Williams syndrome, in: J. Beitchman, N. Cohen, M. Konstantareas, R. Tannock (Eds.), Language, Learning and Behaviour disorders: Developmental, Behavioural and Clinical Perspectives, Cambridge University Press, New York, 1996, pp. 367-392] and conversely, to a global processing bias by others [Psychol. Sci. 10 (1999) 453]. In this study, two identification versions and one drawing version of the Navon hierarchical processing task, a non-verbal task, were employed to investigate this apparent contradiction. The two identification tasks were administered to 21 individuals with WS, 21 typically developing individuals, matched by non-verbal ability, and 21 adult participants matched to the WS group by mean chronological age (CA). The third, drawing task was administered to the WS group and the typically developing (TD) controls only. It was hypothesised that the WS group would show differential processing biases depending on the type of processing the task was measuring. Results from two identification versions of the Navon task measuring divided and selective attention showed that the WS group experienced equal interference from global to local as from local to global levels, and did not show an advantage of one level over another. This pattern of performance was broadly comparable to that of the control groups. The third task, a drawing version of the Navon task, revealed that individuals with WS were significantly better at drawing the local form in comparison to the global figure, whereas the typically developing control group did not show a bias towards either level. In summary, this study demonstrates that individuals with WS do not have a local or a global processing bias when asked to identify stimuli, but do show a local bias in their drawing abilities. This contrast may explain the apparently contrasting findings from previous studies. (C) 2002 Elsevier Science Ltd. All rights reserved.

Attention processes in children with movement difficulties, reading difficulties or both

Reading difficulties (RD) and movement difficulties (MD) co-occur more often in clinical populations than expected for independent disorders. In this study, we investigated the pattern of association between attentional processes, RD and MD in a population of 9 year old school children. Children were screened to identify index groups with RD, MD or both, plus a control group. These groups were then tested on a battery of cognitive attention assessments (TEA-Ch). Results confirmed that the occurrence of RD and MD was greater than would be predicted for independent disorders. Additionally, children with MD, whether or not combined with RD, had poor performance on all attention measures when compared with typically developing children. Children with RD only, were no poorer on measures of attention than typical children. The results are discussed with respect to approaches proposed to account for the co-occurrence of disorders.

Who knows best? Awareness of divided attention difficulty in a neurological rehabilitation setting

Objective: To explore whether patients relearning to walk after acquired brain injury and showing cognitive-motor interference were aware of divided attention difficulty; whether their perceptions concurred with those of treating staff. Design: Patients and neurophysiotherapists (from rehabilitation and disabled wards) completed questionnaires. Factor analyses were applied to responses. Correlations between responses, clinical measures and experimental decrements were examined. Results: Patient/staff responses showed some agreement; staff reported higher levels of perceived difficulty; responses conformed to two factors. One factor (staff/patients alike) reflected expectations about functional/motor status and did not correlate with decrements. The other factor (patients) correlated significantly with dual-task motor decrement, suggesting some genuine awareness of difficulty (cognitive performance prioritized over motor control). The other factor (staff) correlated significantly with cognitive decrement (gait prioritized over sustained attention). Conclusions: Despite some inaccurate estimation of susceptibility; patients and staff do exhibit awareness of divided attention difficulty, but with a limited degree of concurrence. In fact, our results suggest that patients and staff may be sensitive to different aspects of the deficit. Rather than 'Who knows best?', it is a question of 'Who knows what?.

Dissociating word stem completion and cued recall as a function of divided attention at retrieval

The aim of this study was to investigate the widely held, but largely untested, view that implicit memory (repetition priming) reflects an automatic form of retrieval. Specifically, in Experiment 1 we explored whether a secondary task (syllable monitoring), performed during retrieval, would disrupt performance on explicit (cued recall) and implicit (stem completion) memory tasks equally. Surprisingly, despite substantial memory and secondary costs to cued recall when performed with a syllable-monitoring task, the same manipulation had no effect on stem completion priming or on secondary task performance. In Experiment 2 we demonstrated that even when using a particularly demanding version of the stem completion task that incurred secondary task costs, the corresponding disruption to implicit memory performance was minimal. Collectively, the results are consistent with the view that implicit memory retrieval requires little or no processing capacity and is not seemingly susceptible to the effects of dividing attention at retrieval.

Spatial representation and attention in toddlers with Williams syndrome and Down syndrome

The nature of the spatial representations that underlie simple visually guided actions early in life was investigated in toddlers with Williams syndrome (WS), Down syndrome (DS), and healthy chronological age- and mental age-matched controls, through the use of a "double-step" saccade paradigm. The experiment tested the hypothesis that, compared to typically developing infants and toddlers, and toddlers with DS, those with WS display a deficit in using spatial representations to guide actions. Levels of sustained attention were also measured within these groups, to establish whether differences in levels of engagement influenced performance on the double-step saccade task. The results showed that toddlers with WS were unable to combine extra-retinal information with retinal information to the same extent as the other groups, and displayed evidence of other deficits in saccade planning, suggesting a greater reliance on sub-cortical mechanisms than the other populations. Results also indicated that their exploration of the visual environment is less developed. The sustained attention task revealed shorter and fewer periods of sustained attention in toddlers with DS, but not those with WS, suggesting that WS performance on the double-step saccade task is not explained by poorer engagement. The findings are also discussed in relation to a possible attention disengagement deficit in WS toddlers. Our study highlights the importance of studying genetic disorders early in development. (C) 2002 Elsevier Science Ltd. All rights reserved.

Talent in autism: hyper-systemising, hyper-attention to detail and sensory hypersensitivity

We argue that hyper-systemizing predisposes individuals to show talent, and review evidence that hyper-systemizing is part of the cognitive style of people with autism spectrum conditions (ASC). We then clarify the hyper-systemizing theory, contrasting it to the weak central coherence (WCC) and executive dysfunction (ED) theories. The ED theory has difficulty explaining the existence of talent in ASC. While both hyper-systemizing and WCC theories postulate excellent attention to detail, by itself excellent attention to detail will not produce talent. By contrast, the hyper-systemizing theory argues that the excellent attention to detail is directed towards detecting 'if p, then q' rules (or [input-operation-output] reasoning). Such law-based pattern recognition systems can produce talent in systemizable domains. Finally, we argue that the excellent attention to detail in ASC is itself a consequence of sensory hypersensitivity. We review an experiment from our laboratory demonstrating sensory hypersensitivity detection thresholds in vision. We conclude that the origins of the association between autism and talent begin at the sensory level, include excellent attention to detail and end with hyper-systemizing.