General-purpose methods for simulating survival data for expected value of sample information calculations

Background: Expected value of sample information (EVSI) quantifies the expected value to a decision maker of reducing uncertainty by collecting additional data. EVSI calculations require simulating plausible datasets, typically achieved by evaluating quantile functions at random uniform numbers using standard inverse transform sampling (ITS). This is straightforward when closed-form expressions for the quantile function are available, such as for standard parametric survival models, but these are often unavailable when assuming treatment effect waning and for flexible survival models. In these circumstances, the standard ITS method could be implemented by numerically evaluating the quantile functions at each iteration in a probabilistic analysis, but this greatly increases the computational burden. Thus, our study aims to develop general-purpose methods that standardize and reduce the computational burden of the EVSI data-simulation step for survival data. Methods: We developed a discrete sampling method and an interpolated ITS method for simulating survival data from a probabilistic sample of survival probabilities over discrete time units. We compared the general-purpose and standard ITS methods using an illustrative partitioned survival model with and without adjustment for treatment effect waning. Results: The discrete sampling and interpolated ITS methods agree closely with the standard ITS method, with the added benefit of a greatly reduced computational cost in the scenario with adjustment for treatment effect waning. Conclusions: We present general-purpose methods for simulating survival data from a probabilistic sample of survival probabilities that greatly reduce the computational burden of the EVSI data-simulation step when we assume treatment effect waning or use flexible survival models. The implementation of our data-simulation methods is identical across all possible survival models and can easily be automated from standard probabilistic decision analyses

In-sight: an assessment procedure for higher levels of visual functioning for visually impaired children

Contains fulltext : 55358.pdf (publisher's version ) (Closed access)At the Royal Institute for the Education of the Visually Impaired and Blind, an assessment procedure, called In–Sight, has been developed to screen higher levels of visual functioning related to educational process. In–Sight is meant to be used for visually impaired children, 6 to 12 years of age, with normal learning capacities. The instrument has been structured around twelve categories. In March 2005 a study started to determine basic psychometric qualities of the instrument with respect to reliability and validity

Interleukin-6 and interleukin-8 in newborn bacterial infection

The objective of this study is to determine the plasma concentrations and diagnostic accuracy of interleukin-6 (IL-6) and interleukin-8 (IL-8) in newborn infection. One hundred and one newborn infants with clinical signs of infection during their primary hospitalization were investigated with the minimum of a blood culture, C-reactive protein (CRP), full blood examination (FBE), and cytokine concentrations (IL-6 and IL-8). Infection in infants was classified without knowledge of cytokine levels into four groups-definite (n = 11), probable (n = 12), uncertain (n = 52), and nil (n = 26). The median concentrations of IL-6 and IL-8 were significantly higher in the definitely infected group compared with the other three groups (p 175 pg/mL) and IL-8 (>28 pg/mL) had similar sensitivities (80 and 82%, respectively) and specificities (91 and 81%, respectively). Cut-off concentrations could be identified with improved sensitivities (90% for IL-6 and 100% for IL-8) that maintained specificity >50%. However, the confidence intervals were wide for all sensitivities and specificities. IL-6 and IL-8 had little diagnostic accuracy in infants with probable infection. IL-6 and IL-8 concentrations increase early in newborn infants with definite infection

The Tactual Profile: Development of a procedure to assess the tactual functioning of children who are blind

Contains fulltext : 77264.pdf (publisher's version ) (Closed access)The Tactual Profile assesses tactual functioning of children with severe visual impairments between 0 and 16 years of age. The Tactual Profile consists of 430 items, measuring tactile skills required for performing everyday tasks at home and in school. Items are graded according to age level and divided into three domains: tactual sensory, tactual motor and tactual perceptual. The development of the instrument is described and the psychometric properties that were studied reported. Most items had an acceptable difficulty level, and test—retest reliability proved to be good. The analyses for the construct validity showed moderately high correlations between the Tactual Profile and intelligence tests. These correlations were higher for the haptic performance subtests than for the verbal tests. High correlations with other haptic tests were found. However, these associations disappeared after factoring out intelligence, possibly because current methods for examining tactual functioning are strongly affected by intelligence. A summary of work planned in further development of the procedure is provided

Mutations in PCYT2 disrupt etherlipid biosynthesis and cause a complex hereditary spastic paraplegia

CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain