Revisiting youden’s index as a useful measure of the misclassification error in meta-analysis of diagnostic studies

The paper considers meta-analysis of diagnostic studies that use a continuous score for classification of study participants into healthy or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might be confounded by a potentially unknown variation of the cut-off value. To cope with this phenomena it is suggested to use, instead, an overall estimate of the misclassification error previously suggested and used as Youden’s index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel–Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden’s index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.

Revisiting Youden's index as a useful measure of the misclassification error in meta-analysis of diagnostic studies

The paper considers meta-analysis of diagnostic studies that use a continuous Score for classification of study participants into healthy, or diseased groups. Classification is often done on the basis of a threshold or cut-off value, which might vary between Studies. Consequently, conventional meta-analysis methodology focusing solely on separate analysis of sensitivity and specificity might he confounded by a potentially unknown variation of the cut-off Value. To cope with this phenomena it is suggested to use, instead an overall estimate of the misclassification error previously suggested and used as Youden's index and; furthermore, it is argued that this index is less prone to between-study variation of cut-off values. A simple Mantel-Haenszel estimator as a summary measure of the overall misclassification error is suggested, which adjusts for a potential study effect. The measure of the misclassification error based on Youden's index is advantageous in that it easily allows an extension to a likelihood approach, which is then able to cope with unobserved heterogeneity via a nonparametric mixture model. All methods are illustrated at hand of an example on a diagnostic meta-analysis on duplex doppler ultrasound, with angiography as the standard for stroke prevention.

In situ analysis and structural elucidation of sainfoin (Onobrychis viciifolia) tannins for high-throughput germplasm screening

A rapid thiolytic degradation and cleanup procedure was developed for analyzing tannins directly in chlorophyll-containing sainfoin (Onobrychis viciifolia) plants. The technique proved suitable for complex tannin mixtures containing catechin, epicatechin, gallocatechin, and epigallocatechin flavan-3-ol units. The reaction time was standardized at 60 min to minimize the loss of structural information as a result of epimerization and degradation of terminal flavan-3-ol units. The results were evaluated by separate analysis of extractable and unextractable tannins, which accounted for 63.6−113.7% of the in situ plant tannins. It is of note that 70% aqueous acetone extracted tannins with a lower mean degree of polymerization (mDP) than was found for tannins analyzed in situ. Extractable tannins had between 4 and 29 lower mDP values. The method was validated by comparing results from individual and mixed sample sets. The tannin composition of different sainfoin accessions covered a range of mDP values from 16 to 83, procyanidin/prodelphinidin (PC/PD) ratios from 19.2/80.8 to 45.6/54.4, and cis/trans ratios from 74.1/25.9 to 88.0/12.0. This is the first high-throughput screening method that is suitable for analyzing condensed tannin contents and structural composition directly in green plant tissue.

Thiolytic screening method for exploring condensed tannin variation in a unique sainfoin germplasm bank

This EU funded 'HealthyHay'project stablished a sainfoin (Onobrychis vicifolia) germplasm bank at NIAB, Cambridge, with 306 accessions from around the world. A screening method was developed to characterise tannins by thiolytic degradation [1] directly in green plants for the first time. the method was validated by separate analysis of unextractable, extractable and purified tannins using thiolysis, HPLC-GPC and MALDI-TOF MS. Most tannins (58 to 73% of the total) could be recovered after Toyopearl HW50 fractionation with water, aqueous methanol and acetone. the greatest losses during purification occurred amongst larger molecular weight tannins with mean degree of polymerisation (mDP) > 18. The composition of water-,aqueous methanol- and acetone-soluble tannins differed considerably in their mDP and trans/cis ratios, but not in their prodelphinidin/orocyanidin (PD/PC) ratios.

Hamiltonian geophysical fluid dynamics

Hamiltonian dynamics describes the evolution of conservative physical systems. Originally developed as a generalization of Newtonian mechanics, describing gravitationally driven motion from the simple pendulum to celestial mechanics, it also applies to such diverse areas of physics as quantum mechanics, quantum field theory, statistical mechanics, electromagnetism, and optics – in short, to any physical system for which dissipation is negligible. Dynamical meteorology consists of the fundamental laws of physics, including Newton’s second law. For many purposes, diabatic and viscous processes can be neglected and the equations are then conservative. (For example, in idealized modeling studies, dissipation is often only present for numerical reasons and is kept as small as possible.) In such cases dynamical meteorology obeys Hamiltonian dynamics. Even when nonconservative processes are not negligible, it often turns out that separate analysis of the conservative dynamics, which fully describes the nonlinear interactions, is essential for an understanding of the complete system, and the Hamiltonian description can play a useful role in this respect. Energy budgets and momentum transfer by waves are but two examples.

Constructing prehistory: Lithic analysis in the Levantine Epipalaeolithic

This study explores the way in which our picture of the Levantine Epipalaeolithic has been created, investigating the constructs that take us from found objects to coherent narrative about the world. Drawing on the treatment of chipped stone, the fundamental raw material of prehistoric narratives, it examines the use of figurative devices - of metaphor, metonymy, and synecdoche - to make the connection between the world and the words we need to describe it. The work of three researchers is explored in a case study of the Middle Epipalaeolithic with the aim of showing how different research goals and methodologies have created characteristics for the period that are so entrenched in discourse as to have become virtually invisible.Yet the definition of distinct cultures with long-lasting traditions, the identification of two separate ethnic trajectories linked to separate environmental zones, and the analysis of climate as the key driver of change all rest on analytical manoeuvres to transform objects into data.

Proteomic analysis of resting and thrombin-stimulated platelets reveals the translocation and functional relevance of HIP-55 in platelets

The platelet surface is a dynamic interface that changes rapidly in response to stimuli to coordinate the formation of thrombi at sites of vascular injury. Tight control is essential as loss of organisation may result in the inappropriate formation of thrombi (thrombosis) or excessive bleeding. In this paper we describe the comparative analysis of resting and thrombin-stimulated platelet membrane proteomes and associated proteins to identify proteins important to platelet function. Surface proteins were labelled using a biotin tag and isolated by NeurtrAvidin affinity chromatography. Liquid phase IEF and SDS-PAGE were used to separate proteins, and bands of increased intensity in the stimulated platelet fractions were digested and identified by FT-ICR mass spectrometry. Novel proteins were identified along with proteins known to be translocated to the platelet surface. Furthermore, many platelet proteins revealed changes in location associated with function, including G6B and Hip-55. HIP-55 is an SH3-binding protein important in T-cell receptor signalling. Further analysis of HIP-55 revealed that this adaptor protein becomes increasingly associated with both Syk and integrin beta 3 upon platelet activation. Analysis of HIP-55 deficient platelets revealed reduced fibrinogen binding upon thrombin stimulation, suggesting HIP-55 to be an important regulator of platelet function.

Requirements analysis for an e-government system to support multi-organisational collaborative groups

We present a conceptual architecture for a Group Support System (GSS) to facilitate Multi-Organisational Collaborative Groups (MOCGs) initiated by local government and including external organisations of various types. Multi-Organisational Collaborative Groups (MOCGs) consist of individuals from several organisations which have agreed to work together to solve a problem. The expectation is that more can be achieved working in harmony than separately. Work is done interdependently, rather than independently in diverse directions. Local government, faced with solving complex social problems, deploy MOCGs to enable solutions across organisational, functional, professional and juridical boundaries, by involving statutory, voluntary, community, not-for-profit and private organisations. This is not a silver bullet as it introduces new pressures. Each member organisation has its own goals, operating context and particular approaches, which can be expressed as their norms and business processes. Organisations working together must find ways of eliminating differences or mitigating their impact in order to reduce the risks of collaborative inertia and conflict. A GSS is an electronic collaboration system that facilitates group working and can offer assistance to MOCGs. Since many existing GSSs have been primarily developed for single organisation collaborative groups, even though there are some common issues, there are some difficulties peculiar to MOCGs, and others that they experience to a greater extent: a diversity of primary organisational goals among members; different funding models and other pressures; more significant differences in other information systems both technologically and in their use than single organisations; greater variation in acceptable approaches to solve problems. In this paper, we analyse the requirements of MOCGs led by local government agencies, leading to a conceptual architecture for an e-government GSS that captures the relationships between 'goal', 'context', 'norm', and 'business process'. Our models capture the dynamics of the circumstances surrounding each individual representing an organisation in a MOCG along with the dynamics of the MOCG itself as a separate community.

Single-trial event-related potential analysis for brain-computer interfaces

Abstract. Different types of mental activity are utilised as an input in Brain-Computer Interface (BCI) systems. One such activity type is based on Event-Related Potentials (ERPs). The characteristics of ERPs are not visible in single-trials, thus averaging over a number of trials is necessary before the signals become usable. An improvement in ERP-based BCI operation and system usability could be obtained if the use of single-trial ERP data was possible. The method of Independent Component Analysis (ICA) can be utilised to separate single-trial recordings of ERP data into components that correspond to ERP characteristics, background electroencephalogram (EEG) activity and other components with non- cerebral origin. Choice of specific components and their use to reconstruct “denoised” single-trial data could improve the signal quality, thus allowing the successful use of single-trial data without the need for averaging. This paper assesses single-trial ERP signals reconstructed using a selection of estimated components from the application of ICA on the raw ERP data. Signal improvement is measured using Contrast-To-Noise measures. It was found that such analysis improves the signal quality in all single-trials.

The use of trajectory cluster analysis to interpret trace gas measurements at Mace Head, Ireland

A first step in interpreting the wide variation in trace gas concentrations measured over time at a given site is to classify the data according to the prevailing weather conditions. In order to classify measurements made during two intensive field campaigns at Mace Head, on the west coast of Ireland, an objective method of assigning data to different weather types has been developed. Air-mass back trajectories calculated using winds from ECMWF analyses, arriving at the site in 1995–1997, were allocated to clusters based on a statistical analysis of the latitude, longitude and pressure of the trajectory at 12 h intervals over 5 days. The robustness of the analysis was assessed by using an ensemble of back trajectories calculated for four points around Mace Head. Separate analyses were made for each of the 3 years, and for four 3-month periods. The use of these clusters in classifying ground-based ozone measurements at Mace Head is described, including the need to exclude data which have been influenced by local perturbations to the regional flow pattern, for example, by sea breezes. Even with a limited data set, based on 2 months of intensive field measurements in 1996 and 1997, there are statistically significant differences in ozone concentrations in air from the different clusters. The limitations of this type of analysis for classification and interpretation of ground-based chemistry measurements are discussed.

Non-word repetition in adolescents with Specific Language Impairment and Autism plus Language Impairments: a qualitative analysis

Non-word repetition (NWR) was investigated in adolescents with typical development, Specific Language Impairment (SLI) and Autism Plus language Impairment (ALI) (n = 17, 13, 16, and mean age 14;4, 15;4, 14;8 respectively). The study evaluated the hypothesis that poor NWR performance in both groups indicates an overlapping language phenotype (Kjelgaard & Tager-Flusberg, 2001). Performance was investigated both quantitatively, e.g. overall error rates, and qualitatively, e.g. effect of length on repetition, proportion of errors affecting phonological structure, and proportion of consonant substitutions involving manner changes. Findings were consistent with previous research (Whitehouse, Barry, & Bishop, 2008) demonstrating a greater effect of length in the SLI group than the ALI group, which may be due to greater short-term memory limitations. In addition, an automated count of phoneme errors identified poorer performance in the SLI group than the ALI group. These findings indicate differences in the language profiles of individuals with SLI and ALI, but do not rule out a partial overlap. Errors affecting phonological structure were relatively frequent, accounting for around 40% of phonemic errors, but less frequent than straight Consonant-for-Consonant or vowel-for-vowel substitutions. It is proposed that these two different types of errors may reflect separate contributory mechanisms. Around 50% of consonant substitutions in the clinical groups involved manner changes, suggesting poor auditory-perceptual encoding. From a clinical perspective algorithms which automatically count phoneme errors may enhance sensitivity of NWR as a diagnostic marker of language impairment. Learning outcomes: Readers will be able to (1) describe and evaluate the hypothesis that there is a phenotypic overlap between SLI and Autism Spectrum Disorders (2) describe differences in the NWR performance of adolescents with SLI and ALI, and discuss whether these differences support or refute the phenotypic overlap hypothesis, and (3) understand how computational algorithms such as the Levenshtein Distance may be used to analyse NWR data.

Validation of short tandem repeat analysis for the investigation of cases of disputed paternity

This study details validation of two separate multiplex STR systems for use in paternity investigations. These are the Second Generation Multiplex (SGM) developed by the UK Forensic Science Service and the PowerPlex 1 multiplex commercially available from Promega Inc. (Madison, WI, USA). These multiplexes contain 12 different STR systems (two are duplicated in the two systems). Population databases from Caucasian, Asian and Afro-Caribbean populations have been compiled for all loci. In all but two of the 36 STR/ethnic group combinations, no evidence was obtained to indicate inconsistency with Hardy-Weinberg (HW) proportions. Empirical and theoretical approaches have been taken to validate these systems for paternity testing. Samples from 121 cases of disputed paternity were analysed using established Single Locus Probe (SLP) tests currently in use, and also using the two multiplex STR systems. Results of all three test systems were compared and no non-conformities in the conclusions were observed, although four examples of apparent germ line mutations in the STR systems were identified. The data was analysed to give information on expected paternity indices and exclusion rates for these STR systems. The 12 systems combined comprise a highly discriminating test suitable for paternity testing. 99.96% of non-fathers are excluded from paternity on two or more STR systems. Where no exclusion is found, Paternity Index (PI) values of > 10,000 are expected in > 96% of cases.

Analysis of disputed single-parent/child and sibling relationships using 16 STR loci

This study describes the validation of short tandem repeat (STR) systems for the resolution of cases of disputed parentage where only a single parent is available for testing or where the claimed relationship of both parents is in doubt and also cases where sibship must be tested. Three separate multiplex systems the Second Generation Multiplex, Powerplex 1.2 and FFFL have been employed, giving a total of 16 STR loci. Both empirical and theoretical approaches to the validation have been adopted. Appropriate equations have been derived to calculate likelihood ratios for different relationships, incorporating a correction for subpopulation effects. An F(ST) point estimate of 1% has been applied throughout. Empirically, 101 cases of alleged father, alleged mother and child where analysed using six SLP systems and also using the three multiplex STR systems. Of the 202 relationships tested, 197 were independently resolved by both systems, providing either clear evidence of non-parentage or strong support for the relationship.

Techniques for image analysis of movement of juveniles of root-knot nematodes encumbered with Pasteuria penetrans spores

Root-knot nematodes (Meloidogyne spp.) are the most significant plant-parasitic nematodes that damage many crops all over the world. The free-living second stage juvenile (J2) is the infective stage that enters plants. The J2s move in the soil water films to reach the root zone. The bacterium Pasteuria penetrans is an obligate parasite of root-knot nematodes, is cosmopolitan, frequently encountered in many climates and environmental conditions and is considered promising for the control of Meloidogyne spp. The infection potential of P. penetrans to nematodes is well studied but not the attachment effects on the movement of root-knot nematode juveniles, image analysis techniques were used to characterize movement of individual juveniles with or without P. penetrans spores attached to their cuticles. Methods include the study of nematode locomotion based on (a) the centroid body point, (b) shape analysis and (c) image stack analysis. All methods proved that individual J2s without P. penetrans spores attached have a sinusoidal forward movement compared with those encumbered with spores. From these separate analytical studies of encumbered and unencumbered nematodes, it was possible to demonstrate how the presence of P. penetrans spores on a nematode body disrupted the normal movement of the nematode.

Single-cell proteomic analysis of glucosinolate-rich S-cells in Arabidopsis thaliana

Single-cell analysis is essential for understanding the processes of cell differentiation and metabolic specialisation in rare cell types. The amount of single proteins in single cells can be as low as one copy per cell and is for most proteins in the attomole range or below; usually considered as insufficient for proteomic analysis. The development of modern mass spectrometers possessing increased sensitivity and mass accuracy in combination with nano-LC-MS/MS now enables the analysis of single-cell contents. In Arabidopsis thaliana, we have successfully identified nine unique proteins in a single-cell sample and 56 proteins from a pool of 15 single-cell samples from glucosinolate-rich S-cells by nanoLC-MS/MS proteomic analysis, thus establishing the proof-of-concept for true single-cell proteomic analysis. Dehydrin (ERD14_ARATH), two myrosinases (BGL37_ARATH and BGL38_ARATH), annexin (ANXD1_ARATH), vegetative storage proteins (VSP1_ARATH and VSP2_ARATH) and four proteins belonging to the S-adenosyl-l-methionine cycle (METE_ARATH, SAHH1_ARATH, METK4_ARATH and METK1/3_ARATH) with associated adenosine kinase (ADK1_ARATH), were amongst the proteins identified in these single-S-cell samples. Comparison of the functional groups of proteins identified in S-cells with epidermal/cortical cells and whole tissue provided a unique insight into the metabolism of S-cells. We conclude that S-cells are metabolically active and contain the machinery for de novo biosynthesis of methionine, a precursor for the most abundant glucosinolate glucoraphanine in these cells. Moreover, since abundant TGG2 and TGG1 peptides were consistently found in single-S-cell samples, previously shown to have high amounts of glucosinolates, we suggest that both myrosinases and glucosinolates can be localised in the same cells, but in separate subcellular compartments. The complex membrane structure of S-cells was reflected by the presence of a number of proteins involved in membrane maintenance and cellular organisation.