The efficiency of mapping of quantitative trait loci using cofactor analysis in half-sib design

This simulation study was designed to study the power and type I error rate in QTL mapping using cofactor analysis in half-sib designs. A number of scenarios were simulated with different power to identify QTL by varying family size, heritability, QTL effect and map density, and three threshold levels for cofactor were considered. Generally cofactor analysis did not increase the power of QTL mapping in a half-sib design, but increased the type I error rate. The exception was with small family size where the number of correctly identified QTL increased by 13% when heritability was high and 21% when heritability was low. However, in the same scenarios the number of false positives increased by 49% and 45% respectively. With a liberal threshold level of 10% for cofactor combined with a low heritability, the number of correctly identified QTL increased by 14% but there was a 41% increase in the number of false positives. Also, the power of QTL mapping did not increase with cofactor analysis in scenarios with unequal QTL effect, sparse marker density and large QTL effect (25% of the genetic variance), but the type I error rate tended to increase. A priori, cofactor analysis was expected to have higher power than individual chromosome analysis especially in experiments with lower power to detect QTL. Our study shows that cofactor analysis increased the number of false positives in all scenarios with low heritability and the increase was up to 50% in low power experiments and with lower thresholds for cofactors

A short screening instrument for poststroke dementia : the R-CAMCOG

BACKGROUND AND PURPOSE: The CAMCOG is a feasible cognitive screening instrument for dementia in patients with a recent stroke. A major disadvantage of the CAMCOG, however, is its lengthy and relatively complex administration for screening purposes. We therefore developed the Rotterdam CAMCOG (R-CAMCOG), based on the original version. Our aim was to reduce the estimated administration time to 15 minutes or less and to retain or perhaps even improve its diagnostic accuracy. METHODS: We analyzed the item scores on the CAMCOG of 300 consecutive stroke patients, after exclusion of patients with a severe aphasia or lowered consciousness level, who were entered in the Rotterdam Stroke Databank. The diagnosis of dementia was made independent of the R-CAMCOG score, on the basis of clinical examination and neuropsychological test results. The R-CAMCOG was constructed in 3 steps. First, items with floor and ceiling effects were removed. Next, subscales with no additional diagnostic value were excluded. Finally, we removed items that did not contribute to the homogeneity of the subscales. The diagnostic accuracy of the R-CAMCOG and the original CAMCOG was determined by means of the area under the receiver operating characteristic (ROC) curve. RESULTS: In the 3 steps, the number of items was reduced from 59 to 25, divided over the subscales orientation, memory (recent, remote, and learning), perception, and abstraction. The subscale orientation did not reach significance in a logistic regression model but was included in the R-CAMCOG because of its high face validity in dementia screening. Internal validation with ROC analysis suggests that the R-CAMCOG and the CAMCOG are equally accurate in screening for poststroke dementia (area under the curve was 0.95 for both tests). CONCLUSIONS: The R-CAMCOG has overcome the disadvantages of the original CAMCOG. It is a promising, short, and easy-to-administer screening instrument for poststroke dementia. It seems to be sufficiently accurate for this purpose, but the test has yet to be validated in a separate, independent study

Current Progress in Femtosecond Laser Ablation/Ionisation Time-of-Flight Mass Spectrometry

The last decade witnessed considerable progress in the development of laser ablation/ionisation time-of-flight mass spectrometry (LI-TOFMS). The improvement of both the laser ablation ion sources employing femtosecond lasers and the method of ion coupling with the mass analyser led to highly sensitive element and isotope measurements, minimisation of matrix effects, and reduction of various fractionation effects. This improvement of instrumental performance can be attributed to the progress in laser technology and accompanying commercialisation of fs-laser systems, as well as the availability of fast electronics and data acquisition systems. Application of femtosecond laser radiation to ablate the sample causes negligible thermal effects, which in turn allows for improved resolution of chemical surface imaging and depth profiling. Following in the footsteps of its predecessor ns-LIMS, fs-LIMS, which employs fs-laser ablation ion sources, has been developed in the last two decades as an important method of chemical analysis and will continue to improve its performance in subsequent decades. This review discusses the background of fs-laser ablation, overviews the most relevant instrumentation and emphasises their performance figures, and summarizes the studies on several applications, including geochemical, semiconductor, and bio-relevant materials. Improving the chemical analysis is expected by the implementation of laser pulse sequences or pulse shaping methods and shorter laser wavelengths providing current progress in mass resolution achieved in fs-LIMS. In parallel, advancing the methods of data analysis has the potential of making this technique very attractive for 3D chemical analysis with micrometre lateral and sub-micrometre vertical resolution

Improved limit of detection of a high-resolution fs-LIMS instrument through mass-selective beam blanking

Laser Ablation Ionisation Mass Spectrometry (LIMS) is an important quantitative method for chemical analysis of solids. Current limits of detections (LoDs) of LIMS instruments are in the ppm to sub-ppm range (atomic fractions), while other commonly used techniques for solid sample analysis reach LoDs at ppb levels or even below. This study presents the implementation of mass-selective beam blanking in the Laser Mass Spectrometer – Gran Turismo (LMS-GT) to improve the instruments’ detection limit. LMS-GT is a high-performance time-of-flight LIMS instrument coupled to a femtosecond laser ablation ion source reaching micrometre spatial resolutions and mass resolutions 12′000. A fast high voltage switch was developed in-house to induce potential changes at an Einzel lens at the intermediate time focus of the ion trajectory, leading to short deflections of the ion beam and hindering selected species from reaching the detector. The intensities of single mass lines are reduced with 100% efficiency to below the noise floor when blanked. The detector gain can safely be increased while blanking the most intense mass lines simultaneously, thus improving the detection limit. The LoD of LMS-GT prior to the installation of the mass-selective blanking device was at ppm level (at. frac.) with few sub-ppm detections, the installation pushed it to the lower ppb range, without compromising the initial performance. This emphasises that fs-LIMS can be a powerful quantitative technique for the chemical analysis of solids, with the potential to reach the levels of mass spectrometric analysis achievable with Secondary Ion Mass Spectrometry (SIMS) and Laser Ablation–Inductively Coupled Plasma–Mass Spectrometry (LA-ICP-MS)

Recommendations for patient screening in ultra-rare inherited metabolic diseases: what have we learned from Niemann-Pick disease type C?

Rare and ultra-rare diseases (URDs) are often chronic and life-threatening conditions that have a profound impact on sufferers and their families, but many are notoriously difficult to detect. Niemann-Pick disease type C (NP-C) serves to illustrate the challenges, benefits and pitfalls associated with screening for ultra-rare inborn errors of metabolism (IEMs). A comprehensive, non-systematic review of published information from NP-C screening studies was conducted, focusing on diagnostic methods and study designs that have been employed to date. As a key part of this analysis, data from both successful studies (where cases were positively identified) and unsuccessful studies (where the chosen approach failed to identify any cases) were included alongside information from our own experiences gained from the planning and execution of screening for NP-C. On this basis, best-practice recommendations for ultra-rare IEM screening are provided. Twenty-six published screening studies were identified and categorised according to study design into four groups: 1) prospective patient cohort and family-based secondary screenings (18 studies);2) analyses of archived 'biobank' materials (one study);3) medical chart review and bioinformatics data mining (five studies);and 4) newborn screening (two studies). NPC1/NPC2 sequencing was the most common primary screening method (Sanger sequencing in eight studies and next-generation sequencing [gene panel or exome sequencing] in five studies), followed by biomarker analyses (usually oxysterols) and clinical surveillance. Historically, screening for NP-C has been based on single-patient studies, small case series, and targeted cohorts, but the emergence of new diagnostic methods over the last 5-10 years has provided opportunities to screen for NP-C on a larger scale. Combining clinical, biomarker and genetic diagnostic methods represents the most effective way to identify NP-C cases, while reducing the likelihood of misdiagnosis. Our recommendations are intended as a guide for planning screening protocols for ultra-rare IEMs in general

Determination of the microscopic mineralogy of inclusion in an amygdaloidal pillow basalt by fs-LIMS

We present chemical depth profiling studies on mineralogical inclusions embedded in amygdale calcium carbonate by our Laser Ablation Ionisation Mass Spectrometer designed for in situ space research. An IR femtosecond laser ablation is employed to generate ions that are recorded by a miniature time-of-flight mass spectrometer. The mass spectra were measured at several locations on the sample surface and yield chemical depth profiles along the depth length of about 30 mm. The presence of oxides and sulphides within inclusion material allows us to derive elemental abundance calibration factors (relative sensitivity coefficients, RSCs) for major and minor elements. These are obtained from the atomic intensity correlations performed on the depth profiling data. With the RSCs corrections the quantitative analysis of more complex mineralogical phases within the inclusion is conducted by correlating atomic abundance fractions in ternary diagrams, typically used in geology. The spatial resolution of the depth profiles was sufficient to study chemically distinct micrometre-sized objects, such as mineralogical grains and thin layers of minerals including micrometre-sized filamentous structures. The method presented here is well-suited for the quantitative chemical analyses of highly heterogeneous materials where the ablation condition can vary locally with the material composition making the application of standard reference materials less accurate. The presented method is developed to distinguish between abiotic and biological material while searching for micrometre-sized extinct or extent life forms on the surfaces of Solar System bodies

The CAMCOG: a useful screening instrument for dementia in stroke patients

BACKGROUND and PURPOSE: Most mental screening tests focus on the detection of cognitive deficits compatible with Alzheimer's disease. Stroke patients who develop a dementia syndrome, however, constitute a more heterogeneous group with both cortical and subcortical disturbances. We assessed the diagnostic accuracy of the CAMCOG (the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly) and the Mini-Mental State Examination (MMSE) for dementia in patients with a recent stroke. METHODS: In patients age

Impaired Cognitive Functioning in Patients with Tyrosinemia Type I Receiving Nitisinone

ObjectiveTo examine cognitive functioning in patients with tyrosinemia type I treated with nitisinone and a protein-restricted diet.Study designWe performed a cross-sectional study to establish cognitive functioning in children with tyrosinemia type I compared with their unaffected siblings. Intelligence was measured using age-appropriate Wechsler Scales. To assess cognitive development over time, we retrieved sequential IQ scores in a single-center subset of patients. We also evaluated whether plasma phenylalanine and tyrosine levels during treatment was correlated with cognitive development.ResultsAverage total IQ score in 10 patients with tyrosinemia type I receiving nitisinone was significantly lower compared with their unaffected siblings (71 ± 13 vs 91 ± 13; P = .008). Both verbal and performance IQ subscores differed (77 ± 14 vs 95 ± 11; P < .05 and 70 ± 11 vs 87 ± 15; P < .05, respectively). Repeated IQ measurements in a single-center subset of 5 patients revealed a decline in average IQ score over time, from 96 ± 15 to 69 ± 11 (P < .001). No significant association was found between IQ score and either plasma tyrosine or phenylalanine concentration.ConclusionPatients with tyrosinemia type I treated with nitisinone are at risk for impaired cognitive function despite a protein-restricted diet