Utility of Huntington's Disease Assessments by Disease Stage: Floor/Ceiling Effects.
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ABSTRACT:
SUBMITTER: Abreu D
PROVIDER: S-EPMC8320772 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Many clinical measurement tools for balance have ceiling effects. Technology-based assessments using virtual reality systems such as the Computer-Assisted Rehabilitation Environment (CAREN) may provide a way to develop objective, quantitative measures that scale from low to high levels of difficulty. Our objective was to: (1) develop a performance assessment tool (PAT) for the CAREN; (2) quantify the reliability of the tool; (3) validate the scores against clinical balance measures; and (4) compare the scores from a population with balance impairments to those from able-bodied individuals in a cross-sectional validation study. Three games were developed on the CAREN and tested on 49 participants (36 able-bodied and 13 with impaired mobility). For each module, the corresponding measures were transformed into scores using a series of functions such that ceiling and flooring effects would be minimized. The results showed an association between scores and age, an overlap in scores from impaired high-performance individuals and able-bodied low performance individuals, and a correlation of PAT scores with other clinical tests. Several of the limitations of current clinical tools, including floor and ceiling effects, were overcome by the PAT, suggesting that the PAT can be used to monitor the effect of rehabilitation and training.
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Project description:Chemically active particles achieve motility without external forces and torques ("self-propulsion") due to catalytic chemical reactions at their surfaces, which change the chemical composition of the surrounding solution (called "chemical field") and induce hydrodynamic flow of the solution. By coupling the distortions of these fields back to its motion, a chemically active particle experiences an effective interaction with confining surfaces. This coupling can lead to a rich behavior, such as the occurrence of wall-bound steady states of "sliding". Most active particles are density mismatched with the solution and, thus, tend to sediment. Moreover, the often employed Janus spheres, which consist of an inert core material decorated with a cap-like, thin layer of a catalyst, are gyrotactic (i.e., "bottom-heavy"). Whether or not they may exhibit sliding states at horizontal walls depends on the interplay between the active motion and the gravity-driven sedimentation and alignment, such as the gyrotactic tendency to align the axis along the gravity direction being overcome by a competing, activity-driven alignment with a different orientation. It is therefore important to understand and quantify the influence of these gravity-induced effects on the behavior of model chemically active particles moving in the vicinity of walls. For model gyrotactic, self-phoretic Janus particles, here we study theoretically the occurrence of sliding states at horizontal planar walls that are either below ("floor") or above ("ceiling") the particle. We construct "state diagrams" characterizing the occurrence of such states as a function of the sedimentation velocity and of the gyrotactic response of the particle, as well as of the phoretic mobility of the particle. We show that in certain cases sliding states may emerge simultaneously at both the ceiling and the floor, while the larger part of the experimentally relevant parameter space corresponds to particles that would exhibit sliding states only either at the floor or at the ceiling-or there are no sliding states at all. These predictions are critically compared with the results of previous experimental studies, as well as with our dedicated experiments carried out with Pt-coated, polystyrene-core, or silica-core Janus spheres immersed in aqueous hydrogen peroxide solutions.
| S-EPMC7331144 | biostudies-literature
Project description:Goals and methodsA simulation study investigated how ceiling and floor effect (CFE) affect the performance of Welch's t-test, F-test, Mann-Whitney test, Kruskal-Wallis test, Scheirer-Ray-Hare-test, trimmed t-test, Bayesian t-test, and the "two one-sided tests" equivalence testing procedure. The effect of CFE on the estimate of group difference and on its confidence interval, and on Cohen's d and on its confidence interval was also evaluated. In addition, the parametric methods were applied to data transformed with log or logit function and the performance was evaluated. The notion of essential maximum from abstract measurement theory is used to formally define CFE and the principle of maximum entropy was used to derive probability distributions with essential maximum/minimum. These distributions allow the manipulation of the magnitude of CFE through a parameter. Beta, Gamma, Beta prime and Beta-binomial distributions were obtained in this way with the CFE parameter corresponding to the logarithm of the geometric mean. Wald distribution and ordered logistic regression were also included in the study due to their measure-theoretic connection to CFE, even though these models lack essential minimum/maximum. Performance in two-group, three-group and 2 × 2 factor design scenarios was investigated by fixing the group differences in terms of CFE parameter and by adjusting the base level of CFE.Results and conclusionsIn general, bias and uncertainty increased with CFE. Most problematic were occasional instances of biased inference which became more certain and more biased as the magnitude of CFE increased. The bias affected the estimate of group difference, the estimate of Cohen's d and the decisions of the equivalence testing methods. Statistical methods worked best with transformed data, albeit this depended on the match between the choice of transformation and the type of CFE. Log transform worked well with Gamma and Beta prime distribution while logit transform worked well with Beta distribution. Rank-based tests showed best performance with discrete data, but it was demonstrated that even there a model derived with measurement-theoretic principles may show superior performance. Trimmed t-test showed poor performance. In the factor design, CFE prevented the detection of main effects as well as the detection of interaction. Irrespective of CFE, F-test misidentified main effects and interactions on multiple occasions. Five different constellations of main effect and interactions were investigated for each probability distribution, and weaknesses of each statistical method were identified and reported. As part of the discussion, the use of generalized linear models based on abstract measurement theory is recommended to counter CFE. Furthermore, the necessity of measure validation/calibration studies to obtain the necessary knowledge of CFE to design and select an appropriate statistical tool, is stressed.
| S-EPMC6699673 | biostudies-literature
Project description:BACKGROUND:Huntington's Disease (HD) is a hereditary neurodegenerative disorder which affects individuals' ability to walk, talk, think, and reason. Onset is usually in the forties, there are no therapies currently available that alter disease course, and life expectancy is 10-20 years from diagnosis. The gene causing HD is fully penetrant, with a 50% probability of passing the disease to offspring. Although the impacts of HD are substantial, there has been little report of the quality of life of people with the condition in a manner that can be used in economic evaluations of treatments for HD. Health state utility values (HSUVs), used to calculate quality-adjusted life-years (QALYs), are the metric commonly used to inform such healthcare policy decision-making. OBJECTIVES:The aim was to report HSUVs for HD, with specific objectives to use European data to: (i) describe HSUVs by demographic and clinical characteristics; (ii) compare HSUVs of people with HD in the UK with population norms; (iii) identify the relative strength of demographic and clinical characteristics in predicting HSUVs. METHODS:European Huntington's Disease Network REGISTRY study data were used for analysis. This is a multi-centre, multi-national, observational, longitudinal study, which collects six-monthly demographic, clinical, and patient-reported outcome measures, including the SF-36. SF-36 scores were converted to SF-6D HSUVs and described by demographic and clinical characteristics. HSUVs from people with HD in the UK were compared with population norms. Regression analysis was used to estimate the relative strength of age, gender, time since diagnosis, and disease severity (according to the Total Function Capacity (TFC) score, and the UHDRS's Motor score, Behavioural score, and Cognition score) in predicting HSUVs. RESULTS:11,328 questionnaires were completed by 5560 respondents with HD in 12 European countries. Women generally had lower HSUVs than men, and HSUVs were consistently lower than population norms for those with HD in the UK, and dropped with increasing disease severity. The regression model significantly accounted for the variance in SF-6D scores (n?=?1939; F [7,1931]?=?120.05; p?<?0.001; adjusted R-squared 0.3007), with TFC score, Behavioural score, and male gender significant predictors of SF-6D values (p?<?0.001). CONCLUSION:To our knowledge, this is the first report of HSUVs for HD for countries other than the UK, and the first report of SF-6D HSUVs described for 12 European countries, according to demographic and clinical factors. Our analyses provide new insights into the relationships between HD disease characteristics and assessment of health-related quality of life in a form that can be used in policy-relevant economic evaluations.
| S-EPMC6856291 | biostudies-literature
Project description:Huntington's disease (HD) is genetically determined but with variability in symptom onset, leading to uncertainty as to when pharmacological intervention should be initiated. Here we take a computational approach based on neurocognitive phenotyping, computational modeling, and classification, in an effort to provide quantitative predictors of HD before symptom onset. A large sample of subjects-consisting of both pre-manifest individuals carrying the HD mutation (pre-HD), and early symptomatic-as well as healthy controls performed the antisaccade conflict task, which requires executive control and response inhibition. While symptomatic HD subjects differed substantially from controls in behavioral measures [reaction time (RT) and error rates], there was no such clear behavioral differences in pre-HD. RT distributions and error rates were fit with an accumulator-based model which summarizes the computational processes involved and which are related to identified mechanisms in more detailed neural models of prefrontal cortex and basal ganglia. Classification based on fitted model parameters revealed a key parameter related to executive control differentiated pre-HD from controls, whereas the response inhibition parameter declined only after symptom onset. These findings demonstrate the utility of computational approaches for classification and prediction of brain disorders, and provide clues as to the underlying neural mechanisms.
| S-EPMC4752511 | biostudies-literature
Project description:BackgroundSubtle neurodegenerative motor and cognitive impairments accumulate over a prodromal period several years before clinical diagnosis of Huntington's disease (HD). The inclusion of prodromal individuals in therapeutic trials would facilitate testing of therapies early in the disease course and the development of treatments intended to prevent or delay disability.ObjectivesWe evaluate the normalized prognostic index (PIN) score as a tool to select participants for a perimanifest trial. We explore anticipated PIN-based inclusion rates from the preHD screening population and estimate sample-size requirements based on PIN threshold, trial duration, and outcome measure.MethodsIndividual participant data from ENROLL-HD were used to fit mixed effect linear models to assess longitudinal changes in clinical metrics for participants with early-manifest HD and PIN-stratified preHD subcohorts.ResultsA PIN threshold of 0.0 was met by 40% of the preHD participants in ENROLL-HD; 39.4% and 55.2% progressed to new diagnoses of early-manifest HD within 2 and 3 years, respectively. Various PIN thresholds also enabled the selection of specified ratios of prodromal preHD to early manifest HD participants for a perimanifest trial. Estimated sample sizes for a trial enrolling prodromal preHD (PIN > 0.0) and stage 1 and 2 motor-diagnosed participants varied depending on the composition of the screening pool, the length of follow-up (1, 2, or 3 years), and outcome measure.ConclusionsThe composition of a perimanifest clinical trial population can be defined using preselected PIN thresholds, facilitating the assessment of potential disease-modifying therapies in HD. © 2022 Voyager Therapeutics, Inc. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.
| S-EPMC9306552 | biostudies-literature
Project description:OBJECTIVE:Estimates of minimal clinically important improvements (MCIIs) are larger among patients with higher values at baseline, suggesting that these patients require larger changes to appreciate improvements. We examined if baseline dependency of MCIIs was associated with specific patients across three measures, or was owing to floor and ceiling effects. STUDY DESIGN AND SETTING:We prospectively examined 250 outpatients with active rheumatoid arthritis (RA). We used an anchor-based approach to estimate MCIIs for three measures of RA activity (patient global assessment, swollen joint count, and walking time). We examined if the same patients constituted the baseline subgroups with high MCIIs across measures. RESULTS:The MCIIs were greater for those with higher baseline values of all three measures. At the ceiling, there was little opportunity to improve, and judgments were unrelated to measured changes. At midrange, improvements were balanced by worsenings, including some judged as improvements. At the floor, improvements were not similarly balanced. Patients in subgroups with high MCII for patient global assessment were not also predominantly in subgroups with high MCII for the swollen joint count or walking time, and vice versa. CONCLUSION:Variation in MCII by baseline values is because of floor and ceiling effects rather than expectations of particular patients.
| S-EPMC4004715 | biostudies-literature
Project description:The psychometric properties of Patient Reported Outcomes Measurement Information System (PROMIS) instruments have been explored in a number of general and clinical samples. No study, however, has evaluated the psychometric function of these measures in individuals with symptomatic knee osteoarthritis (KOA). The aim of this project was to evaluate the construct (structural) validity and floor/ceiling effects of four PROMIS measures in this population.We conducted a secondary analysis of baseline data from a randomized trial comparing Tai Chi and physical therapy. Participants completed four PROMIS static short-form instruments (i.e., Anxiety, Depression, Physical Function, and Pain Interference) as well as six well-validated (legacy) measures that assess pain, function, and psychological health. We calculated descriptive statistics and percentages of participants scoring the minimum (floor) and maximum (ceiling) possible scores for PROMIS and legacy measures. We also estimated the association between PROMIS scores and scores on legacy measures using Spearman's rank correlations coefficients.Data from 204 participants were analyzed. Mean age of the sample was 60 years; 70% were female. The PROMIS Anxiety and Depression had floor effects with 17 and 24% of participants scoring the minimum, respectively. PROMIS Anxiety and Depression scores had strongest associations with general mental health, including stress (Perceived Stress Scale, r???0.65) and depression (Beck Depression Index-II, r?=?0.70). PROMIS Pain Interference scores correlated most strongly with measures of whole body pain (Short-Form 36 Bodily Pain, r?=?-0.73) and physical health (Short-Form 36 Physical-Component Summary, r?=?-0.73); their correlations were lower with other legacy measures, including with the WOMAC knee-specific pain (r?=?0.47). PROMIS Physical Function scores had stronger associations with scores on the Short-Form 36 Physical Function (r?=?0.79) than with scores on other legacy measures.The four PROMIS static-short forms performed well among individuals with symptomatic knee osteoarthritis as evidenced in correlations with legacy measures. PROMIS Anxiety and Depression target general mental health (e.g., stress, depression), and PROMIS Pain Interference and Physical Function static-short forms target whole-body outcomes among participants with symptomatic knee osteoarthritis. Floor effects in the PROMIS Anxiety and Depression scores should be considered if needing to distinguish among patients with very low levels of these outcomes.Clinicaltrials.gov NCT01258985. Registered 10 December 2010.
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Project description:Beta-lactam antibiotics exhibit high interindividual variability in drug concentrations in patients with critical illness which led to an interest in the use of therapeutic drug monitoring to improve effectiveness and safety. To implement therapeutic drug monitoring, it is necessary to define the beta-lactam therapeutic range-in essence, what drug concentration would prompt a clinician to make dose adjustments up or down. This objective of this narrative review was to summarize evidence for the "floor" (for effectiveness) and "ceiling" (for toxicity) for the beta-lactam therapeutic range to be used with individualized therapeutic drug monitoring.Data sourcesResearch articles were sourced from PubMed using search term combinations of "pharmacokinetics," "pharmacodynamics," "toxicity," "neurotoxicity," "therapeutic drug monitoring," "beta-lactam," "cefepime," "meropenem," "piperacillin/tazobactam," "ICU," and "critical illness."Study selectionArticles were selected if they included preclinical, translational, or clinical data on pharmacokinetic and pharmacodynamic thresholds for effectiveness and safety for beta-lactams in critical illness.Data synthesisExperimental data indicate a beta-lactam concentration above the minimum inhibitory concentration of the organism for greater than or equal to 40-60% of the dosing interval is needed, but clinical data indicate that higher concentrations may be preferrable. In the first 48 hours of critical illness, a free beta-lactam concentration at or above the susceptibility breakpoint of the most likely pathogen for 100% of the dosing interval would be reasonable (typically based on Pseudomonas aeruginosa). After 48 hours, the lowest acceptable concentration could be tailored to 1-2× the observed minimum inhibitory concentration of the organism for 100% of the dosing interval (often a more susceptible organism). Neurotoxicity is the primary dose-dependent adverse effect of beta-lactams, but the evidence remains insufficient to link a specific drug concentration to greater risk.ConclusionsAs studies advance the understanding of beta-lactam exposure and response in critically ill patients, it is essential to clearly define the acceptable therapeutic range to guide regimen selection and adjustment.
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Project description:Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD In this study, we provide evidence that intraventricular administration of GM1 has profound disease-modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L-Ser and D-Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric-like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease-modifying potential in HD.
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