A reformulation of pLSA for uncertainty estimation and hypothesis testing in bio-imaging.

MOTIVATION: Probabilistic latent semantic analysis (pLSA) is commonly applied to describe mass spectra (MS) images. However, the method does not provide certain outputs necessary for the quantitative scientific interpretation of data. In particular, it lacks assessment of statistical uncertainty and the ability to perform hypothesis testing. We show how linear Poisson modelling advances pLSA, giving covariances on model parameters and supporting χ2 testing for the presence/absence of MS signal components. As an example, this is useful for the identification of pathology in MALDI biological samples. We also show potential wider applicability, beyond MS, using magnetic resonance imaging (MRI) data from colorectal xenograft models. RESULTS: Simulations and MALDI spectra of a stroke-damaged rat brain show MS signals from pathological tissue can be quantified. MRI diffusion data of control and radiotherapy-treated tumours further show high sensitivity hypothesis testing for treatment effects. Successful χ2 and degrees-of-freedom are computed, allowing null-hypothesis thresholding at high levels of confidence. AVAILABILITY AND IMPLEMENTATION: Open-source image analysis software available from TINA Vision, www.tina-vision.net. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Quantifying biological samples using Linear Poisson Independent Component Analysis for MALDI-ToF mass spectra.

Motivation: Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI) facilitates the analysis of large organic molecules. However, the complexity of biological samples and MALDI data acquisition leads to high levels of variation, making reliable quantification of samples difficult. We present a new analysis approach that we believe is well-suited to the properties of MALDI mass spectra, based upon an Independent Component Analysis derived for Poisson sampled data. Simple analyses have been limited to studying small numbers of mass peaks, via peak ratios, which is known to be inefficient. Conventional PCA and ICA methods have also been applied, which extract correlations between any number of peaks, but we argue makes inappropriate assumptions regarding data noise, i.e. uniform and Gaussian. Results: We provide evidence that the Gaussian assumption is incorrect, motivating the need for our Poisson approach. The method is demonstrated by making proportion measurements from lipid-rich binary mixtures of lamb brain and liver, and also goat and cow milk. These allow our measurements and error predictions to be compared to ground truth. Availability and implementation: Software is available via the open source image analysis system TINA Vision, www.tina-vision.net. Contact: paul.tar@manchester.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

A new method for the high-precision assessment of tumor changes in response to treatment.

Motivation: Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both development and also in response to treatment. The large variations observed in control group, tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, linear Poisson modeling (LPM) evaluates changes in apparent diffusion co-efficient between baseline and 72 h after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes is compared to those attainable using a conventional t-test analysis on basic apparent diffusion co-efficient distribution parameters. Results: When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4-fold (i.e. equivalent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalized medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes. Availability and implementation: TINA Vision open source software is available from www.tina-vision.net. Supplementary information: Supplementary data are available at Bioinformatics online.

Prediction of the jugular venous waveform using a model of CSF dynamics.

BACKGROUND AND PURPOSE: We have previously reported a model of cerebral hydrodynamics in the form of an equivalent electrical circuit. The aim of this work was to demonstrate that the model could predict venous flow patterns seen in the superior sagittal sinus (SSS), straight sinus (STS), and jugular vein (JV) in normal volunteers. MATERIALS AND METHODS: An electrical equivalence model of CSF and cerebral blood flow was fitted to measured arterial and CSF data from 16 healthy volunteers. Predictions of the venous outflow waveform derived from the model were compared with measured venous flows in the SSS, STS, and JV. RESULTS: The model accurately predicted the measured jugular waveform. The measured waveforms from SSS and STS showed a less pronounced and delayed systolic peak compared with the predicted outflow. The fitted bulk model parameters provided relative values that correspond approximately to the impedance of arterial capillaries (1.0), cerebral aqueduct ( approximately 0), venous capillaries ( approximately 0), and arteries (0.01) and for the elastic capacitance of the ventricles (4.11), capillaries ( approximately 0), and veins (271). The elastic capacitance of the major cerebral arteries was large and could not be accurately determined. CONCLUSIONS: We have confirmed the ability of the model to predict the venous waveforms in healthy persons. The absence of any statistically significant component of the venous waveform not described by the model implies that measurements of venous flow could be used to constrain further the model-fitting process.

Estimating False Positive Contamination in Crater Annotations from Citizen Science Data.

Web-based citizen science often involves the classification of image features by large numbers of minimally trained volunteers, such as the identification of lunar impact craters under the Moon Zoo project. Whilst such approaches facilitate the analysis of large image data sets, the inexperience of users and ambiguity in image content can lead to contamination from false positive identifications. We give an approach, using Linear Poisson Models and image template matching, that can quantify levels of false positive contamination in citizen science Moon Zoo crater annotations. Linear Poisson Models are a form of machine learning which supports predictive error modelling and goodness-of-fits, unlike most alternative machine learning methods. The proposed supervised learning system can reduce the variability in crater counts whilst providing predictive error assessments of estimated quantities of remaining true verses false annotations. In an area of research influenced by human subjectivity, the proposed method provides a level of objectivity through the utilisation of image evidence, guided by candidate crater identifications.

Balance marks cognitive changes in old age because it reflects global brain atrophy and cerebro-arterial blood-flow.

In healthy old age biomarkers such as Balance robustly correlate with measures of mental abilities such as scores on tests of intelligence, reaction times and memory. A plausible explanation is that balance reflects general physiological fitness and so also neurophysiological integrity, but direct evidence is lacking. Brain scans measured age-associated loss of brain volume and cerebro-arterial blood flow (CBf) in 69 volunteers aged from 62 to 81 years who also took the Tinetti Balance test battery, 3 tests of fluid intelligence, 3 tests of decision speed and a memory test. Balance, but not atrophy or CBf, predicted intelligence test scores. Balance, atrophy, and CBf all independently predicted speed and memory scores but, after variance in atrophy and CBf had been considered, predictions from Balance were no longer significant. It appears that in these tests Balance marks cognitive performance in old age because it reflects gross age-related neurophysiological changes.

Right-hemisphere encephalopathy in elderly subjects with schizophrenia: evidence from neuropsychological and brain imaging studies.

RATIONALE: Cognitive impairment is a recognised feature of schizophrenia. Elderly patients with early-acquired schizophrenia are seriously affected, with a proportion of them showing clinically significant dementia, not accounted for by any recognized degenerative processes common in this age group, such as Alzheimer's disease. Progression of cognitive deficits is described in elderly institutionalised patients, but disputed amongst community dwelling subjects. The pattern of cognitive deficits in this age group is not yet clearly defined, although there is some evidence that it differs from that in Alzheimer's disease. There is little evidence of any underlying specific brain abnormality. OBJECTIVES: To characterize the neuropsychological deficits in elderly schizophrenia patients and distinguish them from those in Alzheimer's disease. To establish the presence of underlying structural brain abnormality using MRI. METHODS: Twenty-eight elderly schizophrenia patients with onset before the age of 45 years carried out neuropsychology tests. Twelve scored in the dementia range and were compared with 16 equally impaired patients with early Alzheimer's disease. Thirteen of the schizophrenia patients consented to brain MRI. The imaging data were analysed using a newly developed automated method of measuring CSF volume distributions and compared with data from 30 age-matched normal controls. RESULTS: The schizophrenia group was more impaired on visuo-spatial tasks than the Alzheimer's group but less impaired on corresponding verbal tasks, despite similar overall cognitive impairment. The MR scans revealed right-sided enlargement of ventral CSF spaces in the schizophrenia patients especially in the posterior third, and this correlated with their impaired performance on visuo-spatial tasks. CONCLUSIONS: The results suggest that right hemisphere impairment underlies the specific profile of cognitive impairment in elderly patients with schizophrenia.

Mathematical segmentation of grey matter, white matter and cerebral spinal fluid from MR image pairs.

The aims of this study were (1) to design a mathematical segmentation technique to allow extraction of grey matter, white matter and cerebral spinal fluid volumes from paired high resolution MR images and (2) to document the statistical accuracy of the method with different image combinations. A series of linear equations were derived that describe proportional tissue volumes in individual image voxels. The equations use estimates of pure tissue values to derive the proportion of each tissue within a single voxel. Repeatability of manual estimations of pure tissue values was assessed both using regions of interest and thresholding techniques. Statistical accuracy of tissue estimations for a variety of image pairs was assessed from measurements of root-mean-square noise and mean grey level intensity. The technique was used to produce parametric images of grey and white matter distribution. The segmentation technique showed greatest statistical accuracy when the first image has high grey/white matter contrast and the second image has little contrast or the rank order of the signal intensities from pure tissue is reversed. A combination of inversion recovery fast spin echo and fast FLAIR images produced a statistical error of 11% for grey matter and 10% for white matter for any given voxel. The effect of increasing sample size improves both of these figures to give a 1% statistical error on a 100 pixel sample.

Voxel based analysis of tissue volume from MRI data.

There are many techniques available for the analysis of MRI data. Often these methods are presented as completed algorithms, which specify what processing must be performed, but they are rarely presented in a way which makes clear the assumptions that must hold in order that these algorithms will provide valid results. The aim of this review article is to relate the common forms of algorithms and to explain the assumptions behind them. This is done in the context of the use of quantitative statistical methods, which we understand to be the only self-consistent method for any data analysis. We hope that this will go some way towards helping with the choice of which algorithm to use for particular analysis tasks.

The effects of motion on parametric fMRI analysis techniques.

Subject motion during the time course of functional activation studies has been shown to cause spurious signals which can mimic 'true' activation. Therefore, the importance of motion correction has been widely recognized. Correction with post-processing using image registration software is common practice in functional imaging and analysis. Many image registration algorithms, developed for analysis requirements other than fMRI, assume rigid body motion. Although these techniques are now routinely used by a number of groups, rigid body coregistration has not yet been shown to reduce the effects of motion to an acceptable level in fMRI analysis, i.e. the effects on resulting correlation analysis directly. In this paper we have used volume data to assess rigid body co-registration in terms of motion artefacts for the different correlation approaches used in fMRI. We have developed a new way of visualizing motion effects in correlation analysis based on generating a scatter plot of correlation score against local image gradient. This technique has been tested on fMRI data sets from a functional paradigm suffering from motion correlated artefacts, with and without rigid body motion correction. Although we do not attempt to estimate the actual residual motion, this technique can be used to verify the results of analysis and select regions of relatively unambiguous activation. This paper assesses directly the rigid body assumption and proves the need for, and effectiveness of, co-registration for all correlation based analysis techniques. The specific differences between the popular correlation forms used are investigated and explained. We show that for certain forms of correlation analysis the effects of motion, while not removed altogether, are effectively statistically eliminated.

An integrated simulator for surgery of the petrous bone.

This paper describes work being undertaken as part of the IERAPSI (Integrated Environment for the Rehearsal and Panning of Surgical Intervention) project. The project is focussing on surgery for the petrous bone, and brings together a consortium of European clinicians and technology providers working in this field. The paper presents the results of a comprehensive user task analysis that has been carried out in the first phase of the IERAPSI project, and details the current status of development of a pre operative planning environment and a physically-based surgical simulator.

Alarming prevalence of community-acquired multidrug-resistant organisms colonization in children with cancer and implications for therapy: A prospective study.

BACKGROUND: Infection or colonization with multidrug-resistant organisms (MDRO) is associated with high mortality and morbidity. Knowledge of MDRO colonization may help in planning empirical antibiotic approach in neutropenic patients, which is known to improve patient outcomes. While routine cultures are positive and may help direct antibiotic therapy in only up to 15% neutropenic patients, surveillance cultures are positive in more than 90% of cancer patients. AIMS: To assess the rate of MDRO carrier status at presentation and rate of conversion to MDRO during the treatment. MATERIALS AND METHODS: Rectal swabs of all the outpatients presenting to pediatric oncology unit were sent within 7 days from date of registration from January 2014 to December 2014. Furthermore, stool cultures/rectal swabs of all patients who got directly admitted to the pediatric ward at presentation were sent within 24 h. Repeat rectal swabs were sent again for patients from this cohort when they got readmitted to the ward at least 15 days after last discharge or when clinically indicated. RESULTS: Baseline surveillance rectal swabs were sent for 618 patients, which included 528 children with hematological malignancies and 90 children with solid tumors. Forty-five (7.3%) showed no growth. Of the remaining 573, 197 (34.4%) patients were colonized by two organisms and 30 (5.2%) by three organisms. Three hundred and thirty-four (58.4%) showed extended spectrum beta-lactamase (ESBL) Enterobacteriaceae, of which 165 (49.5%) were ESBL sensitive to beta-lactam with beta-lactamase inhibitors combinations and 169 (50.5%) were resistant to combinations. One hundred and sixteen (20.2%) were carbapenem-resistant Enterobacteriaceae (CRE) and 65 (11.4%) had vancomycin-resistant enterococci in baseline cultures. Only 63 (21%) patients were colonized by a sensitive organism in their baseline surveillance cultures. Morbidity (Intensive Care Unit stay) and mortality was higher in patients colonized by MDR organisms. There was a significant correlation between the place of residence and CRE colonization status with the highest rate (60%) of CRE colonization observed in children from East India. The repeat cultures showed the further conversion of sensitive isolates to MDRO in 80% of these children, of which 40% each converted from non-ESBL and non-CRE to ESBL and CRE, respectively. CONCLUSION: This is the first study illustrating the alarming high prevalence of community-acquired MDRO colonization, especially CRE, which has grave implications for therapy for children with cancer potentially compromising delivery of aggressive chemotherapy and affecting outcomes. This incidence further increases during the course of treatment. Knowing the baseline colonization also guides us for the planning of chemotherapy as well as antibiotic approach and infection control strategies. Local antibiotics stewardship including education of the healthcare workers as well as national level interventions to prevent antibiotic misuse in the community is critical to minimize this problem.

Epidemiology of blood stream infections in pediatric patients at a Tertiary Care Cancer Centre.

BACKGROUND: Blood stream infections (BSI) are among the most common causes of preventable deaths in children with cancer in a developing country. Knowledge of its etiology as well as antibiotic sensitivity is essential not only for planning antimicrobial policy, but also the larger infection prevention and control measures. AIMS: To describe the etiology and sensitivity of BSI in the pediatric oncology unit at a tertiary cancer center. MATERIALS AND METHODS: All the samples representative of BSI sent from pediatric oncology unit during the period of January to December, 2013 were included in the study, and analyzed for microbiological spectrum with their antibiotic sensitivity. RESULTS: A total of 4198 samples were representative of BSI. The overall cultures positivity rate was 6.97% with higher positivity rate (10.28%) from central lines. Of the positive cultures, 208 (70.9%) were Gram-negative bacilli (GNB), 71 (24.2%) were Gram-positive organisms, and 14 (4.7%) were Candida species. Lactose fermenting Enterobacteriaceae i.e., Escherichia coli (28.4%), Klebsiella pneumoniae (22.1%), and Enterobacter (4.8%) accounted for 55.3% of all GNB. Pseudomonas accounted for 53 (25.5%) and Acinetobacter 19 (9.1%) of GNB. Among Gram-positive isolates, staphylococci were the most frequent (47.8%), followed by Streptococcus pneumoniae 17 (23.9%), beta-hemolytic streptococci 11 (15.5%), and enterococci 9 (12.68%). Of GNB, 45.7% were pan-sensitive, 24% extended spectrum beta-lactamase (ESBL) producers, 27% were resistant to carbapenems, and 3.4% resistant to colistin. Pseudomonas was most sensitive, and Klebsiella was least sensitive of GNB. Of the staphylococcal isolates, 41.67% were methicillin-resistant Staphylococcus aureus (MRSA) and 10% of Coagulase Negative Stapylococci (CONS) were methicillin. CONCLUSION: A high degree of ESBL producers and carbapenem-resistant Enterobacteriaceae is concerning; with emerging resistance to colistin, raising the fear of a return to the preantibiotic era. An urgent intervention including creating awareness and establishment of robust infection control and antibiotic stewardship program is the most important need of the hour.

Adverse event following immunization (AEFI) surveillance in India, position paper of Indian Academy of Pediatrics,2013.

Adverse event following immunization (AEFI) is a critical component of immunization program. The risk of AEFI with vaccination is always weighed against the risk of not immunizing a child. There is an evolving AEFI surveillance system in India for the vaccines delivered through universal immunization program (UIP) of government sector, but the reporting remained suboptimal for long in the country, and there is almost no participation from private sector. The AEFI reporting from private sector will provide vital information on the safety of new and underutilized vaccines, not part of the UIP in India. The national guidelines are recently revised and updated. The Indian Academy of Pediatrics believes that pediatricians, especially in private sector have a crucial role to play with reporting of AEFI with newer/underutilized vaccines. Programmatic error, vaccine reaction, injection reactions, coincidental and unknown are the five broad categories of AEFI for programmatic purposes. The serious AEFIs (death, disability, cluster and hospitalization) need to be reported immediately and investigated in detail as per the laid down procedures. Once a serious AEFI happens, primary or urban health centre should be immediately informed by the pediatricians practicing in rural or urban areas, respectively. This advocacy paper from the academy provides guidelines to practitioners on how to report cases, and suggests ways for IAP members to help in ongoing efforts of the government in improving AEFI surveillance in the country. The details about the diagnosis and management of known/expected AEFI with UIP and newer vaccines shall be published later.

A fast, model-independent method for cerebral cortical thickness estimation using MRI.

Several algorithms for measuring the cortical thickness in the human brain from MR image volumes have been described in the literature, the majority of which rely on fitting deformable models to the inner and outer cortical surfaces. However, the constraints applied during the model fitting process in order to enforce spherical topology and to fit the outer cortical surface in narrow sulci, where the cerebrospinal fluid (CSF) channel may be obscured by partial voluming, may introduce bias in some circumstances, and greatly increase the processor time required. In this paper we describe an alternative, voxel based technique that measures the cortical thickness using inversion recovery anatomical MR images. Grey matter, white matter and CSF are identified through segmentation, and edge detection is used to identify the boundaries between these tissues. The cortical thickness is then measured along the local 3D surface normal at every voxel on the inner cortical surface. The method was applied to 119 normal volunteers, and validated through extensive comparisons with published measurements of both cortical thickness and rate of thickness change with age. We conclude that the proposed technique is generally faster than deformable model-based alternatives, and free from the possibility of model bias, but suffers no reduction in accuracy. In particular, it will be applicable in data sets showing severe cortical atrophy, where thinning of the gyri leads to points of high curvature, and so the fitting of deformable models is problematic.

Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly.

A functional brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity-dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long-term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non-verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype-tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed (P = 0.001), delayed recall (P = 0.037) and general intelligence (g) (P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non-demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non-significant trend was observed.

Effect of on-site sanitation on groundwater contamination in basaltic environment--a case study from India.

On-site sanitation is increasingly adopted in urban cities in India. The adoption of on-site sanitation system puts the groundwater resources in the vicinity of the system at a greater risk. Microbial contaminants as well as chemical contaminants like Chloride and Nitrate are generated from human waste. These contaminants travel through the medium and ultimately get in contact with the groundwater. Hence, the groundwater sources are vulnerable to nitrate contamination near the on-site sanitation systems. The present study indicates significant Nitrate and Chloride contamination in samples collected close to on-site sanitation systems. The recommended limit set by the Bureau of Indian standards (BIS) limit of 45 mg/l for Nitrate concentration is also exceeded in few samples. The study indicates that Bacterial as well as Nitrate contamination is more in Monsoon as compared to Summer.