Neurological subtle signs and cognitive development a study in late childhood and adolescence

Introduction and aim—Neurological subtle signs (NSS) are often observed during the neurological examination of children and tend to disappear with age. Their persistence into late adolescence or young adulthood has been related to psychiatric and neurocognitive disorders. To provide a better understanding of their functional basis a longitudinal correlational study with neurocognitive measurements was performed. Methods—We conducted multiple regression and correlation analyses of NSS with demographic and cognitive measures on a subset of 341 healthy children (56% males), taking part in a longitudinal dental study. Participants, whose ages ranged between 11–15 years, at first evaluation, undertook yearly, during five years, a 6-item NSS exam (producing a total score ranging between 0–18) and a comprehensive battery of neurocognitive tests. Effects of age, gender, IQ and 7 neurocognitive factors on NSS were analysed. Results—Over the years, NSS scores correlated consistently with selective attention (Stroop test), motor speed (finger tapping), and visuo-motor speed (pegboard speed). Discussion—These results suggest that the disappearance of NSS in late childhood and adolescence occurs primarily in parallel with the development of motor and visuo-motor functions and secondarily in relation to higher order functions such as selective attention (Stroop) and executive control (B-A Trails difference).info:eu-repo/semantics/publishedVersio

A longitudinal study of neurological soft signs from late childhood into early adulthood

Neurological examination of children includes the screening for soft neurological signs (NSS). There is little knowledge about their evolution during adolescence, except that their lasting presence has been associated with developmental, psychological, and cognitive disorders.We report the results of a NSS exam (assessing gross and fine motor function and the presence of hyperactivity and motor impersistence) over a 5-year period, among a group of healthy children who were followed annually as part of a dental study. Their ages ranged from 11 to 15 years at onset to 14 to 18 years at the end. Participants were divided into four groups by age (younger and older) and sex.At the first evaluation there were 191 males and 150 females. NSS score diminished both with increasing age and follow-up time in both groups, but at different rates in males and females. Females reached the lowest scores two years before the younger subgroup of males.These results show that NSS change rapidly in adolescence and at different rates in males and females, which must be taken into account in clinical contexts. The evolution of NSS suggests that they are a signature of neural development.info:eu-repo/semantics/publishedVersio

Assessment and Implication of Prognostic Imbalance in Randomized Controlled Trials with a Binary Outcome – A Simulation Study

Chance imbalance in baseline prognosis of a randomized controlled trial can lead to over or underestimation of treatment effects, particularly in trials with small sample sizes. Our study aimed to (1) evaluate the probability of imbalance in a binary prognostic factor (PF) between two treatment arms, (2) investigate the impact of prognostic imbalance on the estimation of a treatment effect, and (3) examine the effect of sample size (n) in relation to the first two objectives.We simulated data from parallel-group trials evaluating a binary outcome by varying the risk of the outcome, effect of the treatment, power and prevalence of the PF, and n. Logistic regression models with and without adjustment for the PF were compared in terms of bias, standard error, coverage of confidence interval and statistical power.For a PF with a prevalence of 0.5, the probability of a difference in the frequency of the PF≥5% reaches 0.42 with 125/arm. Ignoring a strong PF (relative risk = 5) leads to underestimating the strength of a moderate treatment effect, and the underestimate is independent of n when n is >50/arm. Adjusting for such PF increases statistical power. If the PF is weak (RR = 2), adjustment makes little difference in statistical inference. Conditional on a 5% imbalance of a powerful PF, adjustment reduces the likelihood of large bias. If an absolute measure of imbalance ≥5% is deemed important, including 1000 patients/arm provides sufficient protection against such an imbalance. Two thousand patients/arm may provide an adequate control against large random deviations in treatment effect estimation in the presence of a powerful PF.The probability of prognostic imbalance in small trials can be substantial. Covariate adjustment improves estimation accuracy and statistical power, and hence should be performed when strong PFs are observed

A comparison of methods to adjust for continuous covariates in the analysis of randomised trials

BACKGROUND: Although covariate adjustment in the analysis of randomised trials can be beneficial, adjustment for continuous covariates is complicated by the fact that the association between covariate and outcome must be specified. Misspecification of this association can lead to reduced power, and potentially incorrect conclusions regarding treatment efficacy. METHODS: We compared several methods of adjustment to determine which is best when the association between covariate and outcome is unknown. We assessed (a) dichotomisation or categorisation; (b) assuming a linear association with outcome; (c) using fractional polynomials with one (FP1) or two (FP2) polynomial terms; and (d) using restricted cubic splines with 3 or 5 knots. We evaluated each method using simulation and through a re-analysis of trial datasets. RESULTS: Methods which kept covariates as continuous typically had higher power than methods which used categorisation. Dichotomisation, categorisation, and assuming a linear association all led to large reductions in power when the true association was non-linear. FP2 models and restricted cubic splines with 3 or 5 knots performed best overall. CONCLUSIONS: For the analysis of randomised trials we recommend (1) adjusting for continuous covariates even if their association with outcome is unknown; (2) keeping covariates as continuous; and (3) using fractional polynomials with two polynomial terms or restricted cubic splines with 3 to 5 knots when a linear association is in doubt

Quality of life and psychosocial wellbeing in youth with neuromuscular disorders who are wheelchair Users: A systematic review

Objective: To investigate quality of life (QoL) and psychosocial wellbeing in youth with Neuromuscular Disorders (NMD) who are wheelchair users. Data Sources: Medline, Embase, CINAHL and PsycINFO (January 2004 to April 2016) and reference lists of retrieved full-text papers. Study Selection: Peer-reviewed studies were included when data describing self-reported QoL and psychosocial wellbeing could be separately understood for those using wheelchairs and aged 12-22 years old. 2058 records were independently screened and potentially eligible papers were obtained and examined by all reviewers. Twelve observational and three qualitative studies met the inclusion criteria. Data Extraction: Population representativeness, measurement tools and outcomes, where possible with comparison groups. Two reviewers independently appraised studies for risk of bias to internal validity and generalisability. Data Synthesis: Heterogeneity of measurement and reporting precluded meta-analysis. Data were cross-sectional only. Compared to same age typically developing peers, physical QoL was scored consistently and significantly lower in youth with NMD, whilst psychosocial QoL was not. Psychosocial QoL was highest in youth non-ambulant since early childhood and in those recruited via single tertiary specialist clinics. Mental health and social participation could not be compared to same age populations. Conclusions: Despite low physical QoL, psychosocial QoL in youth with NMD appeared comparable to same age peers. The psychosocial wellbeing of younger adolescents on degenerative disease trajectories appeared most compromised, though the longitudinal impacts of growing up with NMD on mental health and social participation are unknown. Interpretation was hampered by poor description of participant age, gender and physical ability, lack of population based recruitment strategies and inconsistent use of age appropriate measures. Understanding of self-reported QoL and psychosocial wellbeing in youth with NMD transitioning to adulthood is limited

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio