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Morbidities generally show patterns of concentration that vary by space and time. Disease mapping models are useful in estimating the spatiotemporal patterns of disease risks and are therefore pivotal for effective disease surveillance, resource allocation, and the development of prevention strategies. This study considers six spatiotemporal Bayesian hierarchical models based on two spatial conditional autoregressive priors. It could serve as a guideline on the development and application of Bayesian hierarchical models to assess the emerging risk trends, risk clustering, and spatial inequality trends, with estimation of covariables' effects on the interested disease risk. The method is applied to the Florida Birth Record data between 2006 and 2015 to study two cardiovascular risk factors: preeclampsia and gestational diabetes. High-risk clusters were detected in North Central Florida for preeclampsia and in Central Florida for gestational diabetes. While the adjusted disease trend was stable, spatial inequality peaked in 2011-2012 for both diseases. Exposure to PM2.5 at first or/and second trimester increased the risk of preeclampsia and gestational diabetes, but the magnitude is less severe compared to previous studies. In conclusion, this study underscores the significance of selecting appropriate disease mapping models in estimating the intricate spatiotemporal patterns of disease risk and suggests the importance of localized interventions to reduce health disparities. The result also identified an opportunity to study potential risk factors of preeclampsia, as the spike of risk in North Central Florida cannot be explained by current covariables., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most commonly diagnosed human prion disease caused by the abnormal misfolding of the 'cellular' prion protein (PrP C ) into the transmissible 'scrapie-type' prion form (PrP Sc ). Neuropathologic evaluation of brains with sCJD reveals abnormal PrP Sc deposits primarily in grey matter structures, often associated with micro-vacuolar spongiform changes in neuropil, neuronal loss, and gliosis. Abnormal PrP Sc deposits have also been reported in the retina of patients with sCJD, but few studies have characterized the morphology of these retinal PrP Sc deposits or evaluated for any retinal neurodegenerative changes. We performed histopathologic and morphometric analyses of retinal and brain prion deposits in 14 patients with sCJD. Interestingly, we discovered that the morphology of retinal PrP Sc deposits generally differs from that of brain PrP Sc deposits in terms of size and shape. We found that retinal PrP Sc deposits consistently localize to the outer plexiform layer of the retina. Additionally, we observed that the retinal PrP Sc deposits are not associated with the spongiform change, neuronal loss, and gliosis often seen in the brain. The stereotypic morphology and location of PrP Sc deposits in sCJD retinas may help guide the use of ocular imaging devices in the detection of these deposits for a clinical diagnosis., Competing Interests: Declaration of competing interest None., (Published by Elsevier Ltd.)

Introduction: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, and despite treatment of the primary tumor, approximately 15%-50% of patients will develop metastatic disease. Based on gene expression profiling (GEPs), UM can be categorized as Class 1A (low metastatic risk), Class 1B (intermediate metastatic risk), or Class 2 (high metastatic risk). PReferentially expressed Antigen in MElanoma (PRAME) status is an independent prognostic UM biomarker and a potential target for immunotherapy in metastatic UM. PRAME expression status can be detected in tumors using reverse-transcription polymerase chain reaction (RT-PCR). More recently, immunohistochemistry (IHC) has been developed to detect PRAME protein expression. Here, we employed both techniques to evaluate PRAME expression in 18 UM enucleations., Methods: Tumor material from the 18 UM patients who underwent enucleation was collected by fine-needle aspiration before or during enucleation and sent for GEP and PRAME analysis by RT-PCR. Histologic sections from these patients were stained with an anti-PRAME monoclonal antibody. We collected patient demographics and tumor characteristics and included this with our analysis of GEP class, PRAME status by RT-PCR, and PRAME status by IHC. PRAME IHC and RT-PCR results were compared., Results: Twelve males (12/18) and 6 females (6/18) with an average age of 60.6 years underwent enucleation for UM. TNM staging of the UM diagnosed Stage I in 2 patients (2/18), Stage II in 7 patients (7/18), Stage III in 8 patients (8/18), and Stage IV in 1 (1/18). GEP was Class 1A in 6 tumors (6/18), Class 1B in 6 tumors (6/18), and Class 2 in 6 tumors (6/18). PRAME IHC showed diffusely positive labeling of all UM cells in 2/18 enucleations; negative IHC labeling of UM cells in 9/18 enucleations; and IHC labeling of subsets of UM cells in 7/18 enucleations. Eleven of the 17 UMs tested for PRAME by both RT-PCR and IHC had consistent PRAME results. In the remaining 6/17 cases tested by both modalities, PRAME results were discordant between RT-PCR and IHC., Conclusions: We find that PRAME IHC distinguishes PRAME-positive and PRAME-negative UM tumor cells. Interestingly, IHC reveals focal PRAME expression in subsets of tumor cells consistent with tumor heterogeneity. PRAME RT-PCR and IHC provide concordant results in most of our cases. We suggest that discordance in PRAME results could arise from spatial or temporal variation in PRAME expression between tumor cells. Further studies are required to determine the prognostic implications of PRAME IHC in UM., Competing Interests: All authors: no reported conflicts., (Copyright © 2022 by S. Karger AG, Basel.)

We describe a general approach to transforming molecular models between different levels of resolution, based on machine learning methods. The approach uses a matched set of models at both levels of resolution for training, but requires only the coordinates of their particles and no side information (e.g., templates for substructures, defined mappings, or molecular mechanics force fields). Once trained, the approach can transform further molecular models of the system between the two levels of resolution in either direction with equal facility.

Human mesenchymal stem cells (hMSCs) are widely represented in regenerative medicine clinical strategies due to their compatibility with autologous implantation. Effective bone regeneration involves crosstalk between macrophages and hMSCs, with macrophages playing a key role in the recruitment and differentiation of hMSCs. However, engineered biomaterials able to simultaneously direct hMSC fate and modulate macrophage phenotype have not yet been identified. A novel combinatorial chemistry-topography screening platform, the ChemoTopoChip, is used here to identify materials suitable for bone regeneration by screening 1008 combinations in each experiment for human immortalized mesenchymal stem cell (hiMSCs) and human macrophage response. The osteoinduction achieved in hiMSCs cultured on the "hit" materials in basal media is comparable to that seen when cells are cultured in osteogenic media, illustrating that these materials offer a materials-induced alternative to osteo-inductive supplements in bone-regeneration. Some of these same chemistry-microtopography combinations also exhibit immunomodulatory stimuli, polarizing macrophages towards a pro-healing phenotype. Maximum control of cell response is achieved when both chemistry and topography are recruited to instruct the required cell phenotype, combining synergistically. The large combinatorial library allows us for the first time to probe the relative cell-instructive roles of microtopography and material chemistry which we find to provide similar ranges of cell modulation for both cues. Machine learning is used to generate structure-activity relationships that identify key chemical and topographical features enhancing the response of both cell types, providing a basis for a better understanding of cell response to micro topographically patterned polymers., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Current treatments for chronic pain rely largely on opioids despite their substantial side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing. In particular, a hereditary loss-of-function mutation in Na V 1.7, a sodium channel protein associated with signaling in nociceptive sensory afferents, leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence and structural similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 in primary afferents via epigenome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins at the spinal level as a potential treatment for chronic pain. Toward this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells and then, by the lumbar intrathecal route, delivered both epigenome engineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain, and BzATP-induced pain. Our results show effective repression of Na V 1.7 in lumbar dorsal root ganglia, reduced thermal hyperalgesia in the inflammatory state, decreased tactile allodynia in the neuropathic state, and no changes in normal motor function in mice. We anticipate that this long-lasting analgesia via targeted in vivo epigenetic repression of Na V 1.7 methodology we dub pain LATER, might have therapeutic potential in management of persistent pain states., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

In a previous contribution, a new Riemannian shape space, named TPS space, was introduced to perform statistics on shape data. This space was endowed with a Riemannian metric and a flat connection, with torsion, compatible with the given metric. This connection allows the definition of a Parallel Transport of the deformation compatible with the three-fold decomposition in spherical, deviatoric, and non-affine components. Such a parallel transport also conserves the Γ-energy, strictly related to the total elastic strain energy stored by the body in the original deformation. A new approach is here presented in order to calculate the bending energy on the body alone (body bending energy) and to restrict it exclusively within physical boundaries of objects involved in the deformation analysis. The novelty of this new procedure resides in the fact that we propose a new metric to be preserved during the TPS direct transport. This allows transporting the shape change more coherently with the mechanical meaning of the deformation. The geometry of the TPS space is then further discussed in order to better represent the relationship between the Γ-energy, the strain energy, and the so-called bending energy densities., (© 2019 John Wiley & Sons, Ltd.)

Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two manufacturing techniques, spray-drying and melt extrusion. Each formulation underwent a six-month stability study at accelerated conditions, 40 °C and 75% relative humidity (RH). Significant differences in times to crystallization (onset of crystallization) were observed between both the different polymers and the two processing methods. Stability from zero days to over one year was observed. The extensive experimental data set obtained from this stability study was used to build multiple linear regression models to correlate physicochemical properties of the active pharmaceutical ingredients (API) with the stability data. The purpose of these models is to indicate which combination of processing method and polymer carrier is most likely to give a stable solid dispersion. Six quantitative mathematical multiple linear regression-based models were produced based on selection of the most influential independent physical and chemical parameters from a set of 33 possible factors, one model for each combination of polymer and processing method, with good predictability of stability. Three general rules are proposed from these models for the formulation development of suitably stable solid dispersions. Namely, increased stability is correlated with increased glass transition temperature ( T g ) of solid dispersions, as well as decreased number of H-bond donors and increased molecular flexibility (such as rotatable bonds and ring count) of the drug molecule.

In landmarks-based Shape Analysis size is measured, in most cases, with Centroid Size. Changes in shape are decomposed in affine and non affine components. Furthermore the non affine component can be in turn decomposed in a series of local deformations (partial warps). If the extent of deformation between two shapes is small, the difference between Centroid Size and m-Volume increment is barely appreciable. In medical imaging applied to soft tissues bodies can undergo very large deformations, involving large changes in size. The cardiac example, analyzed in the present paper, shows changes in m-Volume that can reach the 60%. We show here that standard Geometric Morphometrics tools (landmarks, Thin Plate Spline, and related decomposition of the deformation) can be generalized to better describe the very large deformations of biological tissues, without losing a synthetic description. In particular, the classical decomposition of the space tangent to the shape space in affine and non affine components is enriched to include also the change in size, in order to give a complete description of the tangent space to the size-and-shape space. The proposed generalization is formulated by means of a new Riemannian metric describing the change in size as change in m-Volume rather than change in Centroid Size. This leads to a redefinition of some aspects of the Kendall's size-and-shape space without losing Kendall's original formulation. This new formulation is discussed by means of simulated examples using 2D and 3D platonic shapes as well as a real example from clinical 3D echocardiographic data. We demonstrate that our decomposition based approaches discriminate very effectively healthy subjects from patients affected by Hypertrophic Cardiomyopathy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Most functional MRI (fMRI) studies map task-driven brain activity using a block or event-related paradigm. Sparse paradigm free mapping (SPFM) can detect the onset and spatial distribution of BOLD events in the brain without prior timing information, but relating the detected events to brain function remains a challenge. In this study, we developed a decoding method for SPFM using a coordinate-based meta-analysis method of activation likelihood estimation (ALE). We defined meta-maps of statistically significant ALE values that correspond to types of events and calculated a summation overlap between the normalized meta-maps and SPFM maps. As a proof of concept, this framework was applied to relate SPFM-detected events in the sensorimotor network (SMN) to six motor functions (left/right fingers, left/right toes, swallowing, and eye blinks). We validated the framework using simultaneous electromyography (EMG)-fMRI experiments and motor tasks with short and long duration, and random interstimulus interval. The decoding scores were considerably lower for eye movements relative to other movement types tested. The average successful rate for short and long motor events were 77 ± 13% and 74 ± 16%, respectively, excluding eye movements. We found good agreement between the decoding results and EMG for most events and subjects, with a range in sensitivity between 55% and 100%, excluding eye movements. The proposed method was then used to classify the movement types of spontaneous single-trial events in the SMN during resting state, which produced an average successful rate of 22 ± 12%. Finally, this article discusses methodological implications and improvements to increase the decoding performance. Hum Brain Mapp 38:5778-5794, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Root architecture impacts water and nutrient uptake efficiency. Identifying exactly which root architectural properties influence these agronomic traits can prove challenging. In this paper, approximately 300 wheat (Triticum aestivum) plants were divided into four groups using two binary classifications, high versus low nitrogen uptake efficiency (NUpE), and high versus low nitrate in the growth medium. The root system architecture for each wheat plant was captured using 16 quantitative variables. The multivariate analysis tool, linear discriminant analysis, was used to construct composite variables, each a linear combination of the original variables, such that the score of the plants on the new variables showed the maximum between-group variability. The results show that the distribution of root-system architecture traits differs between low- and high-NUpE plants and, less strongly, between low-NUpE plants grown on low versus high nitrate media., (© The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

The purpose of this study was to develop a predictive model of the amorphous stability of drugs with particular relevance for poorly water-soluble compounds. Twenty-five representative neutral poorly soluble compounds with a diverse range of physicochemical properties and chemical structures were systematically selected from an extensive library of marketed drug products. The physical stability of the amorphous form, measured over a 6 month period by the onset of crystallization of amorphous films prepared by melting and quench-cooling, was assessed using polarized light microscopy. The data were used as a response variable in a statistical model with calculated/predicted or measured molecular, thermodynamic, and kinetic parameters as explanatory variables. Several multiple linear regression models were derived, with varying balance between calculated/predicted and measured parameters. It was shown that inclusion of measured parameters significantly improves the predictive ability of the model. The best model demonstrated a prediction accuracy of 82% and included the following as parameters: melting and glass transition temperatures, enthalpy of fusion, configurational free energy, relaxation time, number of hydrogen bond donors, lipophilicity, and the ratio of carbon to heteroatoms. Good predictions were also obtained with a simpler model, which was comprised of easily acquired quantities: molecular weight and enthalpy of fusion. Statistical models are proposed to predict long-term amorphous drug stability. The models include readily accessible parameters, which are potentially the key factors influencing amorphous stability. The derived models can support faster decision making in drug formulation development.

We consider the problem of comparing sizes and shapes of objects when landmark data are prone to measurement error. We show that naive implementation of ordinary Procrustes analysis that ignores measurement error can compromise inference. To account for measurement error, we propose the conditional score method for matching configurations, which guarantees consistent inference under mild model assumptions. The effects of measurement error on inference from naive Procrustes analysis and the performance of the proposed method are illustrated via simulation and application in three real data examples. Supplementary materials for this article are available online.

This is a discussion of the paper: 'Overview of object oriented data analysis' by J. Steve Marron and Andrés M. Alonso., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

fMRI studies of brain activity at rest study slow (<0.1 Hz) intrinsic fluctuations in the blood-oxygenation-level-dependent (BOLD) signal that are observed in a temporal scale of several minutes. The origin of these fluctuations is not clear but has previously been associated with slow changes in rhythmic neuronal activity resulting from changes in cortical excitability or neuronal synchronization. In this work, we show that individual spontaneous BOLD events occur during rest, in addition to slow fluctuations. Individual spontaneous BOLD events were identified by deconvolving the hemodynamic impulse response function for each time point in the fMRI time series, thus requiring no information on timing or a-priori spatial information of events. The patterns of activation detected were related to the motor, visual, default-mode, and dorsal attention networks. The correspondence between spontaneous events and slow fluctuations in these networks was assessed using a sliding window, seed-correlation analysis, where seed regions were selected based on the individual spontaneous event BOLD activity maps. We showed that the correlation varied considerably over time, peaking at the time of spontaneous events in these networks. By regressing spontaneous events out of the fMRI signal, we showed that both the correlation strength and the power in spectral frequencies <0.1 Hz decreased, indicating that spontaneous activation events contribute to low-frequency fluctuations observed in resting state networks with fMRI. This work provides new insights into the origin of signals detected in fMRI studies of functional connectivity., (Copyright © 2011 Wiley Periodicals, Inc.)

The ability to detect single trial responses in functional magnetic resonance imaging (fMRI) studies is essential, particularly if investigating learning or adaptation processes or unpredictable events. We recently introduced paradigm free mapping (PFM), an analysis method that detects single trial blood oxygenation level dependent (BOLD) responses without specifying prior information on the timing of the events. PFM is based on the deconvolution of the fMRI signal using a linear hemodynamic convolution model. Our previous PFM method (Caballero-Gaudes et al., 2011: Hum Brain Mapp) used the ridge regression estimator for signal deconvolution and required a baseline signal period for statistical inference. In this work, we investigate the application of sparse regression techniques in PFM. In particular, a novel PFM approach is developed using the Dantzig selector estimator, solved via an efficient homotopy procedure, along with statistical model selection criteria. Simulation results demonstrated that, using the Bayesian information criterion to select the regularization parameter, this method obtains high detection rates of the BOLD responses, comparable with a model-based analysis, but requiring no information on the timing of the events and being robust against hemodynamic response function variability. The practical operation of this sparse PFM method was assessed with single-trial fMRI data acquired at 7T, where it automatically detected all task-related events, and was an improvement on our previous PFM method, as it does not require the definition of a baseline state and amplitude thresholding and does not compromise on specificity and sensitivity., (Copyright © 2011 Wiley Periodicals, Inc.)

A general framework for a novel non-geodesic decomposition of high-dimensional spheres or high-dimensional shape spaces for planar landmarks is discussed. The decomposition, principal nested spheres, leads to a sequence of submanifolds with decreasing intrinsic dimensions, which can be interpreted as an analogue of principal component analysis. In a number of real datasets, an apparent one-dimensional mode of variation curving through more than one geodesic component is captured in the one-dimensional component of principal nested spheres. While analysis of principal nested spheres provides an intuitive and flexible decomposition of the high-dimensional sphere, an interesting special case of the analysis results in finding principal geodesics, similar to those from previous approaches to manifold principal component analysis. An adaptation of our method to Kendall's shape space is discussed, and a computational algorithm for fitting principal nested spheres is proposed. The result provides a coordinate system to visualize the data structure and an intuitive summary of principal modes of variation, as exemplified by several datasets.

The placenta is an essential component of the life-support system for the developing foetus, enabling nutrients and waste to be exchanged between the foetal and maternal circulations. Maternal blood flows between the densely packed branches of villous trees, within which are foetal vessels. Here, we explore some of the challenges in modelling maternal haemodynamic transport using homogenization approaches. We first show how two measures can be used to estimate the minimum distance over which the distribution of villous branches appears statistically homogeneous. We then analyse a simplified model problem (solute transport by a unidirectional flow past a distribution of point sinks) to assess the accuracy of homogenization approximations as a function of governing parameters (Péclet and Damköhler numbers) and the statistical properties of the sink distribution. The difference between the leading-order homogenization approximation and the exact solute distribution is characterized by large spatial gradients at the scale of individual villi and substantial fluctuations that can be correlated over lengthscales comparable to the whole domain. This study highlights the importance of quantifying errors owing to spatial disorder in multi-scale approximations of physiological systems.

This work presents a novel method of mapping the brain's response to single stimuli in space and time without prior knowledge of the paradigm timing: paradigm free mapping (PFM). This method is based on deconvolution of the hemodynamic response from the voxel time series assuming a linear response and using a ridge-regression algorithm. Statistical inference is performed by defining a spatio-temporal t-statistic and by controlling for multiple comparisons using the false discovery rate procedure. The methodology was validated on five subjects who performed self-paced and visually cued finger tapping at 7 Tesla, with moderate (TR = 2 s) and high (TR = 0.4 s) temporal resolution. The results demonstrate that detection of single-trial BOLD events is feasible without a priori information on the stimulus paradigm. The proposed method opens up the possibility of designing temporally unconstrained paradigms to study the cortical response to unpredictable mental events., (Copyright © 2010 Wiley-Liss, Inc.)

Some methods for the statistical analysis of surface shapes and asymmetry are introduced. We focus on a case study where magnetic resonance images of the brain are available from groups of 30 schizophrenia patients and 38 controls, and we investigate large-scale brain surface shape differences. Key aspects of shape analysis are to remove nuisance transformations by registration and to identify which parts of one object correspond with the parts of another object. We introduce maximum likelihood and Bayesian methods for registering brain images and providing large-scale correspondences of the brain surfaces. Brain surface size-and-shape analysis is considered using random field theory, and also dimension reduction is carried out using principal and independent components analysis. Some small but significant differences are observed between the the patient and control groups. We then investigate a particular type of asymmetry called torque. Differences in asymmetry are observed between the control and patient groups, which add strength to other observations in the literature. Further investigations of the midline plane location in the 2 groups and the fitting of nonplanar curved midlines are also considered.

Faces are assumed to be unique, but their use in court has remained problematic as no method of comparison with known error rates has been accepted by the scientific community. Rather than relying on the assumed uniqueness of facial features, previous research has been directed at estimations of face shape frequency. Here, the influence of age, sex, and ancestry on variation was investigated. Statistical shape analysis was used to examine the necessity for sub-divisions in forensic comparisons, using a large sample of facial images on which 30 anthropometric landmark points had been placed in 3D. Results showed a clear pattern of separation of the sexes in all age groups, and in different age groups in men. It was concluded that sub-division of databases by sex will be necessary in forensic comparisons. Sub-division by age may be necessary in men (although not necessarily in women), and may be necessary by ancestry.

Background: Microarrays are a powerful tool used for the determination of global RNA expression. There is an increasing requirement to focus on profiling gene expression in tissues where it is difficult to obtain large quantities of material, for example individual tissues within organs such as the root, or individual isolated cells. From such samples, it is difficult to produce the amount of RNA required for labelling and hybridisation in microarray experiments, thus a process of amplification is usually adopted. Despite the increasing use of two-cycle amplification for transcriptomic analyses on the Affymetrix ATH1 array, there has been no report investigating any potential bias in gene representation that may occur as a result., Results: Here we compare transcriptomic data generated using Affymetrix one-cycle (standard labelling protocol), two-cycle (small-sample protocol) and IVT-Express protocols with the Affymetrix ATH1 array using Arabidopsis root samples. Results obtained with each protocol are broadly similar. However, we show that there are 35 probe sets (of a total of 22810) that are misrepresented in the two-cycle data sets. Of these, 33 probe sets were classed as mis-amplified when comparisons of two independent publicly available data sets were undertaken., Conclusions: Given the unreliable nature of the highlighted probes, we caution against using data associated with the corresponding genes in analyses involving transcriptomic data generated with two-cycle amplification protocols. We have shown that the Affymetrix IVT-E labelling protocol produces data with less associated bias than the two-cycle protocol, and as such, would recommend this kit for new experiments that involve small samples.

Improvement of methods for evidential facial comparison for the Courts relies on the collection of large databases of facial images that permit the analysis of face shape variation and the development of statistical tools. In this paper, we present a short description and key findings of an anthropometric study of face shape variation in three-dimensions. We used Statistical Shape Analysis to investigate a large database sample (n = 1968), classified by age and gender. We found that size, shape of the bilateral features and midline contributed successively to overall variation. Face size is associated with age. Sexual dimorphism is evident in size and shape, and shows patterns that affect male and female subjects differently. We anticipate this approach will lend itself to the development of methods for analysis of variation within subject groups and the establishment of the relative uniqueness or abundance of facial measurements within them.

Molecular-dynamics simulations of a normal DNA duplex show that breathing events typically occur on the microsecond time scale. This paper analyzes a 12 base pairs DNA duplex containing the "rogue" base difluorotoluene (F) in place of a thymine base (T), for which the breathing events occur on the nanosecond time scale. Starting from a nonlinear Klein-Gordon lattice model and adding noise and damping, we obtain a mesoscopic model of the DNA duplex close to that observed in experiments and all-atom molecular dynamics simulations. The mesoscopic model is calibrated to data from the all-atom molecular dynamics package AMBER for a variety of twist angles of the DNA duplex. Defects are considered in the interchain interactions as well as in the along-chain interactions. This paper also discusses the role of the fluctuation-dissipation relations in the derivation of reduced (mesoscopic) models, the differences between the potential of mean force and the potential energies used in Klein-Gordon lattices, and how breathing can be viewed as competition between the along-chain elastic energy and the interchain binding energy.

Familial correlations in the spinal shape of children are explored using statistical shape analysis. Measurements of the spine on the surface of the back were taken using an optical device, and recorded for several hundred children from the Leeds area of the U.K. A portion of the spine from the distal thoracic to proximal lumbar spine was used for the analysis, and measures of the shape of the spine line were determined using Procrustes analysis and principal components (PCs) analysis. Analysis was carried out on scans repeated in triplicate and scans taken six months apart, and good repeatability was demonstrated. Four groups of children were considered in the main study: monozygotic twins, dizygotic twins, same sex siblings and different sex siblings. Intra-familial correlations were calculated for the shape measures, and also for age and sex matched unrelated controls. The second PC score (which measures possible lordosis) had significant positive correlation in the family groups. It was observed that the familial correlations were higher for the genetically closer groups. Also, the same sex siblings had higher correlation than the different sex siblings. All sibling groups showed greater correlation of sagittal profile for the second PC score than unrelated controls. A significant correlation was observed in same sex pairings for the control data. This work suggests that some elements of spinal profile may be familial but also shows correlation with sex. Both of these observations may be important in the aetiology of idiopathic scoliosis., (Copyright (c) 2007 John Wiley & Sons, Ltd.)

We consider Bayesian methodology for comparing two or more unlabeled point sets. Application of the technique to a set of steroid molecules illustrates its potential utility involving the comparison of molecules in chemoinformatics and bioinformatics. We initially match a pair of molecules, where one molecule is regarded as random and the other fixed. A type of mixture model is proposed for the point set coordinates, and the parameters of the distribution are a labeling matrix (indicating which pairs of points match) and a concentration parameter. An important property of the likelihood is that it is invariant under rotations and translations of the data. Bayesian inference for the parameters is carried out using Markov chain Monte Carlo simulation, and it is demonstrated that the procedure works well on the steroid data. The posterior distribution is difficult to simulate from, due to multiple local modes, and we also use additional data (partial charges on atoms) to help with this task. An approximation is considered for speeding up the simulation algorithm, and the approximating fast algorithm leads to essentially identical inference to that under the exact method for our data. Extensions to multiple molecule alignment are also introduced, and an algorithm is described which also works well on the steroid data set. After all the steroid molecules have been matched, exploratory data analysis is carried out to examine which molecules are similar. Also, further Bayesian inference for the multiple alignment problem is considered.

Purpose: Currently known serum biomarkers do not predict clinical outcome in melanoma. S100-beta is widely established as a reliable prognostic indicator in patients with advanced metastatic disease but is of limited predictive value in tumor-free patients. This study was aimed to determine whether molecular profiling of the serum proteome could discriminate between early- and late-stage melanoma and predict disease progression., Patients and Methods: Two hundred five serum samples from 101 early-stage (American Joint Committee on Cancer [AJCC] stage I) and 104 advanced stage (AJCC stage IV) melanoma patients were analyzed by matrix-assisted laser desorption/ionisation (MALDI) time-of-flight (ToF; MALDI-ToF) mass spectrometry utilizing protein chip technology and artificial neural networks (ANN). Serum samples from 55 additional patients after complete dissection of regional lymph node metastases (AJCC stage III), with 28 of 55 patients relapsing within the first year of follow-up, were analyzed in an attempt to predict disease recurrence. Serum S100-beta was measured using a sandwich immunoluminometric assay., Results: Analysis of 205 stage I/IV serum samples, utilizing a training set of 94 of 205 and a test set of 15 of 205 samples for 32 different ANN models, revealed correct stage assignment in 84 (88%) of 96 of a blind set of 96 of 205 serum samples. Forty-four (80%) of 55 stage III serum samples could be correctly assigned as progressors or nonprogressors using random sample cross-validation statistical methodologies. Twenty-three (82%) of 28 stage III progressors were correctly identified by MALDI-ToF combined with ANN, whereas only six (21%) of 28 could be detected by S100-beta., Conclusion: Validation of these findings may enable proteomic profiling to become a valuable tool for identifying high-risk melanoma patients eligible for adjuvant therapeutic interventions.