Qualitative System Identification from Imperfect Data

Experience in the physical sciences suggests that the only realistic means of understanding complex systems is through the use of mathematical models. Typically, this has come to mean the identification of quantitative models expressed as differential equations. Quantitative modelling works best when the structure of the model (i.e., the form of the equations) is known; and the primary concern is one of estimating the values of the parameters in the model. For complex biological systems, the model-structure is rarely known and the modeler has to deal with both model-identification and parameter-estimation. In this paper we are concerned with providing automated assistance to the first of these problems. Specifically, we examine the identification by machine of the structural relationships between experimentally observed variables. These relationship will be expressed in the form of qualitative abstractions of a quantitative model. Such qualitative models may not only provide clues to the precise quantitative model, but also assist in understanding the essence of that model. Our position in this paper is that background knowledge incorporating system modelling principles can be used to constrain effectively the set of good qualitative models. Utilising the model-identification framework provided by Inductive Logic Programming (ILP) we present empirical support for this position using a series of increasingly complex artificial datasets. The results are obtained with qualitative and quantitative data subject to varying amounts of noise and different degrees of sparsity. The results also point to the presence of a set of qualitative states, which we term kernel subsets, that may be necessary for a qualitative model-learner to learn correct models. We demonstrate scalability of the method to biological system modelling by identification of the glycolysis metabolic pathway from data

Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate

BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required

Consequences of fractal grade distribution for bulk sorting of a copper porphyry deposit

We show the presence of fractal ordering of copper grade in bore core data at short range in the Cadia Ridgeway porphyry deposit and measure its persistence after mining by monitoring the output of the mine every 20 s for a month using a large scale, zero field magnetic resonance sensor. A simple model is used to investigate this connection and its consequences for sorting of the ore. Fractal distributions, and their associated power laws, have two features highly favourable for segregating ore: a large proportion of low-grade pods and the large scale spatial clustering of grad

Functional outcomes from a head-to-head, randomized, double-blind trial of lisdexamfetamine dimesylate and atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder and an inadequate response to methylphenidate

Attention-deficit/hyperactivity disorder (ADHD) is associated with functional impairments in multiple domains of patients' lives. A secondary objective of this randomized, active-controlled, head-to-head, double-blind, dose-optimized clinical trial was to compare the effects of lisdexamfetamine dimesylate (LDX) and atomoxetine (ATX) on functional impairment in children and adolescents with ADHD. Patients aged 6-17 years with an ADHD Rating Scale IV total score ≥ 28 and an inadequate response to methylphenidate treatment (judged by investigators) were randomized (1:1) to once-daily LDX or ATX for 9 weeks. Parents/guardians completed the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P) at baseline and at week 9 or early termination. p values were nominal and not corrected for multiple comparisons. Of 267 randomized patients, 200 completed the study (LDX 99, ATX 101). At baseline, mean WFIRS-P total score in the LDX group was 0.95 [standard deviation (SD) 0.474; 95% confidence interval (CI) 0.87, 1.03] and in the ATX group was 0.91 (0.513; 0.82, 1.00). Scores in all WFIRS-P domains improved from baseline to endpoint in both groups, with least-squares mean changes in total score of -0.35 (95% CI -0.42, -0.29) for LDX and -0.27 (-0.33, -0.20) for ATX. The difference between LDX and ATX was statistically significant (p < 0.05) for the Learning and School (effect size of LDX vs ATX, 0.43) and Social Activities (0.34) domains and for total score (0.27). Both treatments reduced functional impairment in children and adolescents with ADHD; LDX was statistically significantly more effective than ATX in two of six domains and in total score

Association between methylphenidate treatment and risk of seizure: A population-based self-controlled case series study

Background: Individuals with attention-deficit hyperactivity disorder (ADHD) are at increased risk of seizures. Stimulant medications such as methylphenidate are the most commonly prescribed treatment for ADHD, but the association between their therapeutic use and the risk of seizures is unclear. We aimed to investigate the association between methylphenidate treatment and the risk of seizure. Methods: For this population-based observational study, we used the electronic medical record database of the Hong Kong Clinical Data Analysis And Reporting System to identify individuals aged 6–25 years who received at least one methylphenidate prescription during the study period. Individuals with records of seizure or epilepsy before the study period were excluded. Individuals treated with methylphenidate who had seizures during the study period were included in the subsequent analyses, and a self-controlled case-series design was used to control for time-invariant individual characteristics. We did additional analyses using skin infection as a negative control outcome. We compared relative incidence of seizure during periods when individuals were exposed to methylphenidate with that during non-exposed periods. Findings: Of 29 604 individuals prescribed methylphenidate between Jan 1, 2001, and Dec 31, 2017, 269 (199 males and 70 females) had incident seizures. The mean age at baseline was 6·66 years (SD 2·01) and the median age at the incident seizure was 9·69 years (IQR 7·62–12·99). The overall incidence of seizure during methylphenidate treatment was 4·4 per 10 000 patient-years. We detected an increased risk of seizure during the first 30 days of methylphenidate treatment compared with that during non-exposed periods, with an incidence rate ratio of 4·01 (95% CI 2·09–7·68). No increase in risk was identified during the following 31–180 days of treatment (1·13, 0·56–2·25) or during subsequent treatment (1·38, 0·92–2·07). We did not identify an increased risk in any risk window for the negative control outcome analysis. No individuals died because of a seizure during the study period. Interpretation: The incidence of seizures was higher in the period immediately after the start of methylphenidate treatment than in the non-exposed period. No increased risk was observed during continuation of methylphenidate treatment. The association between methylphenidate treatment and seizures immediately after initiation of medication can be seen as a potential safety signal. Monitoring of neurological outcomes in individuals with ADHD is recommended when they first start methylphenidate treatment. Funding: Hong Kong Research Grants Council

Methylphenidate for ADHD in children and adolescents:throwing the baby out with the bathwater

Item does not contain fulltextA recent Cochrane review assessed the efficacy of methylphenidate for attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Notwithstanding the moderate-to-large effect sizes for ADHD symptom reduction found in the meta-analysis, the authors concluded that the quality of the evidence is low and therefore the true magnitude of these effects remains uncertain. We identified a number of major concerns with the review, in the domains of study inclusion, approaches to quality assessment and interpretation of data relating to serious adverse events as well as of the clinical implications of the reported effects. We also found errors in the extraction of data used to estimate the effect size of the primary outcome. Considering all the shortcomings, the conclusion in the Cochrane review that the status of the evidence is uncertain is misplaced. Professionals, parents and patients should refer to previous reviews and existing guidelines, which include methylphenidate as one of the safe and efficacious treatment strategies for ADHD

Cold- and light-induced changes in the transcriptome of wheat leading to phase transition from vegetative to reproductive growth

<p>Abstract</p> <p>Background</p> <p>For plants to flower at the appropriate time, they must be able to perceive and respond to various internal and external cues. Wheat is generally a long-day plant that will go through phase transition from vegetative to floral growth as days are lengthening in spring and early summer. In addition to this response to day-length, wheat cultivars may be classified as either winter or spring varieties depending on whether they require to be exposed to an extended period of cold in order to become competent to flower. Using a growth regime to mimic the conditions that occur during a typical winter in Britain, and a microarray approach to determine changes in gene expression over time, we have surveyed the genes of the major pathways involved in floral transition. We have paid particular attention to wheat orthologues and functional equivalents of genes involved in the phase transition in <it>Arabidopsis</it>. We also surveyed all the MADS-box genes that could be identified as such on the Affymetrix genechip wheat genome array.</p> <p>Results</p> <p>We observed novel responses of several genes thought to be of major importance in vernalisation-induced phase transition, and identified several MADS-box genes that might play an important role in the onset of flowering. In addition, we saw responses in genes of the Gibberellin pathway that would indicate that this pathway also has some role to play in phase transition.</p> <p>Conclusion</p> <p>Phase transition in wheat is more complex than previously reported, and there is evidence that day-length has an influence on genes that were once thought to respond exclusively to an extended period of cold.</p

Evidence against pain specificity in the dorsal posterior insula

The search for a pain centre in the brain has long eluded neuroscientists. Although many regions of the brain have been shown to respond to painful stimuli, all of these regions also respond to other types of salient stimuli. In a recent paper, Segerdahl et al. (Nature Neuroscience, 2015) claims that the dorsal posterior insula (dpIns) is a pain-specific region based on the observation that the magnitude of regional cerebral blood flow (rCBF) fluctuations in the dpIns correlated with the magnitude of evoked pain. However, such a conclusion is, simply, not justified by the experimental evidence provided. Here we discuss three major factors that seriously question this claim

Cowhage-Induced Itch as an Experimental Model for Pruritus. A Comparative Study with Histamine-Induced Itch

Histamine is the prototypical pruritogen used in experimental itch induction. However, in most chronic pruritic diseases, itch is not predominantly mediated by histamine. Cowhage-induced itch, on the other hand, seems more characteristic of itch occurring in chronic pruritic diseases.We tested the validity of cowhage as an itch-inducing agent by contrasting it with the classical itch inducer, histamine, in healthy subjects and atopic dermatitis (AD) patients. We also investigated whether there was a cumulative effect when both agents were combined.Fifteen healthy individuals and fifteen AD patients were recruited. Experimental itch induction was performed in eczema-free areas on the volar aspects of the forearm, using different itch inducers: histamine, cowhage and their combination thereof. Itch intensity was assessed continuously for 5.5 minutes after stimulus application using a computer-assisted visual analogue scale (COVAS).In both healthy and AD subjects, the mean and peak intensity of itch were higher after the application of cowhage compared to histamine, and were higher after the combined application of cowhage and histamine, compared to histamine alone (p<0.0001 in all cases). Itch intensity ratings were not significantly different between healthy and AD subjects for the same itch inducer used; however AD subjects exhibited a prolonged itch response in comparison to healthy subjects (p<0.001).Cowhage induced a more intense itch sensation compared to histamine. Cowhage was the dominant factor in itch perception when both pathways were stimulated in the same time. Cowhage-induced itch is a suitable model for the study of itch in AD and other chronic pruritic diseases, and it can serve as a new model for testing antipruritic drugs in humans