Comparing Machine Learning Classifiers for Predicting Hospital Readmission of Heart Failure Patients in Rwanda.

High rates of hospital readmission and the cost of treating heart failure (HF) are significant public health issues globally and in Rwanda. Using machine learning (ML) to predict which patients are at high risk for HF hospital readmission 20 days after their discharge has the potential to improve HF management by enabling early interventions and individualized treatment approaches. In this paper, we compared six different ML models for this task, including multi-layer perceptron (MLP), K-nearest neighbors (KNN), logistic regression (LR), decision trees (DT), random forests (RF), and support vector machines (SVM) with both linear and radial basis kernels. The outputs of the classifiers are compared using performance metrics including the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. We found that RF outperforms all the remaining models with an AUC of 94% while SVM, MLP, and KNN all yield 88% AUC. In contrast, DT performs poorly, with an AUC value of 57%. Hence, hospitals in Rwanda can benefit from using the RF classifier to determine which HF patients are at high risk of hospital readmission.

A Feature-based Affine Registration Method for Capturing Background Lung Tissue Deformation for Ground Glass Nodule Tracking.

Lung nodule tracking assessment relies on cross-sectional measurements of the largest lesion profile depicted in initial and follow-up computed tomography (CT) images. However, apparent changes in nodule size assessed via simple image-based measurements may also be compromised by the effect of the background lung tissue deformation on the GGN between the initial and follow-up images, leading to erroneous conclusions about nodule changes due to disease. To compensate for the lung deformation and enable consistent nodule tracking, here we propose a feature-based affine registration method and study its performance vis-a-vis several other registration methods. We implement and test each registration method using both a lung- and a lesion-centered region of interest on ten patient CT datasets featuring twelve nodules, including both benign and malignant GGO lesions containing pure GGNs, part-solid, or solid nodules. We evaluate each registration method according to the target registration error (TRE) computed across 30 - 50 homologous fiducial landmarks surrounding the lesions and selected by expert radiologists in both the initial and follow-up patient CT images. Our results show that the proposed feature-based affine lesion-centered registration yielded a 1.1 ± 1.2 mm TRE, while a Symmetric Normalization deformable registration yielded a 1.2 ± 1.2 mm TRE, and a least-square fit registration of the 30-50 validation fiducial landmark set yielded a 1.5 ± 1.2 mm TRE. Although the deformable registration yielded a slightly higher registration accuracy than the feature-based affine registration, it is significantly more computationally efficient, eliminates the need for ambiguous segmentation of GGNs featuring ill-defined borders, and reduces the susceptibility of artificial deformations introduced by the deformable registration, which may lead to increased similarity between the registered initial and follow-up images, over-compensating for the background lung tissue deformation, and, in turn, compromising the true disease-induced nodule change assessment. We also assessed the registration qualitatively, by visual inspection of the subtraction images, and conducted a pilot pre-clinical study that showed the proposed feature-based lesion-centered affine registration effectively compensates for the background lung tissue deformation between the initial and follow-up images and also serves as a reliable baseline registration method prior to assessing lung nodule changes due to disease.

Pairwise versus Transitive Inverse Consistent Longitudinal Rigid Registration of Magnetic Resonance Images of Athletes With Repetitive Non-Concussive Head Injuries: Effects on Regional Distributions of Diffusion Measures.

Accurate alignment of longitudinal diffusion weighted imaging (DWI) scans of a subject is necessary to investigate longitudinal changes in DWI-derived diffusion measures such as fractional anisotropy (FA), mean diffusivity (MD), and quantitative anisotropy (QA). Currently, studies investigating these changes in the context of repetitive non-concussive head injuries (RHIs) perform pairwise rigid registration of all scans of a subject to the first scan or any other reference scan or template. Prajapati et.al 1 show that this strategy of performing pairwise rigid registration lead to a discrepancy in the rigid transformations. To eliminate this discrepancy, they propose performing transitive inverse consistent rigid registration of the longitudinal scans, and they analyze the impact of this approach on the mean values of the local/regional estimates of these diffusion measures. In this work, we further analyze the impact of transitive inverse consistent rigid registration on the distributions (CDFs) of the local/regional estimates of diffusion measures. We identify the regions (among the 48 anatomically defined regions by the JHU DTI-based white matter atlas2,3) that show significant differences in the CDFs obtained using pairwise inverse consistent and transitive inverse consistent rigid registration by performing the two sided Kolmogorov-Smirnov(KS) hypothesis test. We find that for MD and QA, there are certain subjects that have five or more regions with significant differences in the CDFs. Further, these are the same subjects for which Prajapati et.al 1 found regions with 2%-4% differences in the mean values of these diffusion measures. Thus, our results further strengthen the recommendation made by Prajapati et.al 1 to employ transitive inverse consistent rigid registration when investigating local/regional longitudinal changes in diffusion measures.

Transitive Inverse Consistent Rigid Longitudinal Registration of Diffusion Weighted Magnetic Resonance Imaging: A Case Study in Athletes With Repetitive Non-Concussive Head Injuries.

Significant longitudinal changes in metrics derived from diffusion weighted magnetic resonance (MR) images of the brain have been observed in athletes subject to repetitive non-concussive head injuries (RHIs). Accurate alignment of longitudinal scans of a subject is an important step in detecting and quantifying these changes. Currently, tools such as DSI Studio [1], FreeSurfer [2], and FSL [3] perform pairwise rigid registration of all scans in a longitudinal sequence to the first time-point scan (or to another reference scan or template). While the rigid transformations obtained using this strategy can be computed in a manner that enforces inverse consistency, for the case of three or more scans, the transformations are not transitive. This can lead to discrepancy in the rigid transformations that can be measured in physical units. Using a diffusion MRI dataset collected and analyzed as part of a larger study in [4], [5], [6], we illustrate this discrepancy, and we show how it can lead to uncertainty in local/regional estimates of diffusion metrics including fractional anistropy (FA), mean diffusivity (MD), and quantitatve anisotropy (QA). Additionally, we propose a method to perform transitive longitudinal rigid registration of a sequence of scans in a manner that guarantees that the discrepancy in the transformations will be eliminated.Clinical relevance- This paper establishes that standard processing pipelines for performing longitudinal analysis of diffusion MR images of the brain exhibit registration discrepancies that can be eliminated.

Evaluating the sensitivity of SARS-CoV-2 infection rates on college campuses to wastewater surveillance.

As college campuses reopened in fall 2020, we saw a large-scale experiment unfold on the efficacy of various strategies to contain the SARS-CoV-2 virus. Traditional individual surveillance testing via nasal swabs and/or saliva is among the measures that colleges are pursuing to reduce the spread of the virus on campus. Additionally, some colleges are testing wastewater on their campuses for signs of infection, which can provide an early warning signal for campuses to locate COVID-positive individuals. However, a representation of wastewater surveillance has not yet been incorporated into epidemiological models for college campuses, nor has the efficacy of wastewater screening been evaluated relative to traditional individual surveillance testing, within the structure of these models. Here, we implement a new model component for wastewater surveillance within an established epidemiological model for college campuses. We use a hypothetical residential university to evaluate the efficacy of wastewater surveillance for maintaining low infection rates. We find that wastewater sampling with a 1-day lag to initiate individual screening tests, plus completing the subsequent tests within a 4-day period can keep overall infections within 5% of the infection rates seen with traditional individual surveillance testing. Our results also indicate that wastewater surveillance can effectively reduce the number of false positive cases by identifying subpopulations for surveillance testing where infectious individuals are more likely to be found. Through a Monte Carlo risk analysis, we find that surveillance testing that relies solely on wastewater sampling can be fragile against scenarios with high viral reproductive numbers and high rates of infection of campus community members by outside sources. These results point to the practical importance of additional surveillance measures to limit the spread of the virus on campus and the necessity of a proactive response to the initial signs of outbreak.

Progesterone Treatment Does Not Decrease Serum Levels of Biomarkers of Glial and Neuronal Cell Injury in Moderate and Severe Traumatic Brain Injury Subjects: A Secondary Analysis of the Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (ProTECT) III Trial.

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury.

Deep Volumetric Segmentation of Murine Cochlear Compartments from Micro-Computed Tomography Images.

Local drug delivery to the inner ear via micropump implants has the potential to be much more effective than oral drug delivery for treating patients with sensorineural hearing loss and to protect hearing from ototoxic insult due to noise exposure or cancer treatments. Designing micropumps to deliver appropriate concentrations of drugs to the necessary cochlear compartments is of paramount importance; however, directly measuring local drug concentrations over time throughout the cochlea is not possible. Recent approaches for indirectly quantifying local drug concentrations in animal models capture a series of magnetic resonance (MR) or micro computed tomography (µCT) images before and after infusion of a contrast agent into the cochlea. These approaches require accurately segmenting important cochlear components (scala tympani (ST), scala media (SM) and scala vestibuli (SV)) in each scan and ensuring that they are registered longitudinally across scans. In this paper, we focus on segmenting cochlear compartments from µCT volumes using V-Net, a convolutional neural network (CNN) architecture for 3-D segmentation. We show that by modifying the V-Net architecture to decrease the numbers of encoder and decoder blocks and to use dilated convolutions enables extracting local estimates of drug concentration that are comparable to those extracted using atlas-based segmentation (3.37%, 4.81%, and 19.65% average relative error in ST, SM, and SV), but in a fraction of the time. We also test the feasibility of training our network on a larger MRI dataset, and then using transfer learning to perform segmentation on a smaller number of µCT volumes, which would enable this technique to be used in the future to characterize drug delivery in the cochlea of larger mammals.

Cochlear pharmacokinetics - Micro-computed tomography and learning-prediction modeling for transport parameter determination.

Inner ear disorders such as sensorineural deafness and genetic diseases may one day be treated with local drug delivery to the inner ear. Current pharmacokinetic models have been based on invasive methods to measure drug concentrations, limiting them in spatial resolution, and restricting the research to larger rodents. We developed an intracochlear pharmacokinetic model based on an imaging, learning-prediction (LP) paradigm for learning transport parameters in the murine cochlea. This was achieved using noninvasive micro-computed tomography imaging of the cochlea during in vivo infusion of a contrast agent at the basal end of scala tympani through a cochleostomy. Each scan was registered in 3-D to a cochlear atlas to segment the cochlear regions with high accuracy, enabling concentrations to be extracted along the length of each scala. These spatio-temporal concentration profiles were used to learn a concentration dependent diffusion coefficient, and transport parameters between the major scalae and to clearance. The LP model results are comparable to the current state of the art model, and can simulate concentrations for cases involving different infusion molecules and different drug delivery protocols. Forward simulation results with pulsatile delivery suggest the pharmacokinetic model can be used to optimize drug delivery protocols to reduce total drug delivered and the potential for toxic side effects. While developed in the challenging murine cochlea, the processes are scalable to larger animals and different drug infusion paradigms.

Toward an Affine Feature-Based Registration Method for Ground Glass Lung Nodule Tracking.

Lung nodule progression assessment from medical imaging is a critical biomarker for assessing the course of the disease or the patient's response to therapy. CT images are routinely used to identify the location and size and rack the progression of lung nodules. However, nodule segmentation is challenging and prone to error, due to the irregular nodule boundaries, therefore introducing error in the lung nodule quantification process. Here, we describe the development and evaluation of a feature-based affine image registration framework that enables us to register two time point thoracic CT images as a means to account for the back-ground lung tissue deformation, then use digital subtraction images to assess tumor progression/regression. We have demonstrated this method on twelve de-identified patient datasets and showed that the proposed method yielded a better than 1.5mm registration accuracy vis-à-vis the widely accepted non-rigid image registration techniques. To demonstrate the potential clinical value of our described technique, we conducted a study in which our collaborating clinician was asked to provide an assessment of nodule progression/regression using the digital subtraction images post-registration. This assessment was consistent, yet provided more confidence, than the traditional lung nodule tracking based on visual analysis of the CT images.

Inter-Method Discrepancies in Brain Volume Estimation May Drive Inconsistent Findings in Autism.

Previous studies applying automatic preprocessing methods on Structural Magnetic Resonance Imaging (sMRI) report inconsistent neuroanatomical abnormalities in Autism Spectrum Disorder (ASD). In this study we investigate inter-method differences as a possible cause behind these inconsistent findings. In particular, we focus on the estimation of the following brain volumes: gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and total intra cranial volume (TIV). T1-weighted sMRIs of 417 ASD subjects and 459 typically developing controls (TDC) from the ABIDE dataset were estimated using three popular preprocessing methods: SPM, FSL, and FreeSurfer (FS). Brain volumes estimated by the three methods were correlated but had significant inter-method differences; except TIVSPM vs. TIVFS, all inter-method differences were significant. ASD vs. TDC group differences in all brain volume estimates were dependent on the method used. SPM showed that TIV, GM, and CSF volumes of ASD were larger than TDC with statistical significance, whereas FS and FSL did not show significant differences in any of the volumes; in some cases, the direction of the differences were opposite to SPM. When methods were compared with each other, they showed differential biases for autism, and several biases were larger than ASD vs. TDC differences of the respective methods. After manual inspection, we found inter-method segmentation mismatches in the cerebellum, sub-cortical structures, and inter-sulcal CSF. In addition, to validate automated TIV estimates we performed manual segmentation on a subset of subjects. Results indicate that SPM estimates are closest to manual segmentation, followed by FS while FSL estimates were significantly lower. In summary, we show that ASD vs. TDC brain volume differences are method dependent and that these inter-method discrepancies can contribute to inconsistent neuroimaging findings in general. We suggest cross-validation across methods and emphasize the need to develop better methods to increase the robustness of neuroimaging findings.

Sex and Age Effects of Functional Connectivity in Early Adulthood.

Functional connectivity (FC) in resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to find coactivating regions in the human brain. Despite its widespread use, the effects of sex and age on resting FC are not well characterized, especially during early adulthood. Here we apply regression and graph theoretical analyses to explore the effects of sex and age on FC between the 116 AAL atlas parcellations (a total of 6670 FC measures). rs-fMRI data of 494 healthy subjects (203 males and 291 females; age range: 22-36 years) from the Human Connectome Project were analyzed. We report the following findings. (1) Males exhibited greater FC than females in 1352 FC measures (1025 survived Bonferroni correction; [Formula: see text]). In 641 FC measures, females exhibited greater FC than males but none survived Bonferroni correction. Significant FC differences were mainly present in frontal, parietal, and temporal lobes. Although the average FC values for males and females were significantly different, FC values of males and females exhibited large overlap. (2) Age effects were present only in 29 FC measures and all significant age effects showed higher FC in younger subjects. Age and sex differences of FC remained significant after controlling for cognitive measures. (3) Although sex [Formula: see text] age interaction did not survive multiple comparison correction, FC in females exhibited a faster cross-sectional decline with age. (4) Male brains were more locally clustered in all lobes but the cerebellum; female brains had a higher clustering coefficient at the whole-brain level. Our results indicate that although both male and female brains show small-world network characteristics, male brains were more segregated and female brains were more integrated. Findings of this study further our understanding of FC in early adulthood and provide evidence to support that age and sex should be controlled for in FC studies of young adults.

Divide and Conquer: Sub-Grouping of ASD Improves ASD Detection Based on Brain Morphometry.

Low success (<60%) in autism spectrum disorder (ASD) classification using brain morphometry from the large multi-site ABIDE dataset and inconsistent findings on brain morphometric abnormalities in ASD can be attributed to the ASD heterogeneity. In this study, we show that ASD brain morphometry is highly heterogeneous, and demonstrate that the heterogeneity can be mitigated and classification improved if autism severity (AS), verbal IQ (VIQ) and age are used with morphometric features. Morphometric features from structural MRIs (sMRIs) of 734 males (ASD: 361, controls: 373) of ABIDE were derived using FreeSurfer. Applying the Random Forest classifier, an AUC of 0.61 was achieved. Adding VIQ and age to morphometric features, AUC improved to 0.68. Sub-grouping the subjects by AS, VIQ and age improved the classification with the highest AUC of 0.8 in the moderate-AS sub-group (AS = 7-8). Matching subjects on age and/or VIQ in each sub-group further improved the classification with the highest AUC of 0.92 in the low AS sub-group (AS = 4-5). AUC decreased with AS and VIQ, and was the lowest in the mid-age sub-group (13-18 years). The important features were mainly from the frontal, temporal, ventricular, right hippocampal and left amygdala regions. However, they highly varied with AS, VIQ and age. The curvature and folding index features from frontal, temporal, lingual and insular regions were dominant in younger subjects suggesting their importance for early detection. When the experiments were repeated using the Gradient Boosting classifier similar results were obtained. Our findings suggest that identifying brain biomarkers in sub-groups of ASD can yield more robust and insightful results than searching across the whole spectrum. Further, it may allow identification of sub-group specific brain biomarkers that are optimized for early detection and monitoring, increasing the utility of sMRI as an important tool for early detection of ASD.

The predictive power of structural MRI in Autism diagnosis.

Diagnosis of Autism Spectrum Disorder (ASD) using structural magnetic resonance imaging (sMRI) of the brain has been a topic of significant research interest. Previous studies using small datasets with well-matched Typically Developing Controls (TDC) report high classification accuracies (80-96%) but studies using the large heterogeneous ABIDE dataset report accuracies less than 60%. In this study we investigate the predictive power of sMRI in ASD using 373 ASD and 361 TDC male subjects from the ABIDE. Brain morphometric features were derived using FreeSurfer and classification was performed using three different techniques: Random Forest (RF), Support Vector Machine (SVM) and Gradient Boosting Machine (GBM). Although high classification accuracies were possible in individual sites (with a maximum of 97% in Caltech), the highest classification accuracy across all sites was only 60% (sensitivity = 57%, specificity = 64%). However, the accuracy across all sites improved to 67% when IQ and age information were added to morphometric features. Across all three classifiers, volume and surface area had more discriminative power. In general, important features for classification were present in the frontal and temporal regions and these regions have been implicated in ASD. This study also explores the effect of demographics and behavioral measures on the predictive power of sMRI. Results show that classification accuracy increases with autism severity and that ASD detection with sMRI is easier before the age of 10 years.

ICA-fNORM: Spatial Normalization of fMRI Data Using Intrinsic Group-ICA Networks.

A common pre-processing challenge associated with group level fMRI analysis is spatial registration of multiple subjects to a standard space. Spatial normalization, using a reference image such as the Montreal Neurological Institute brain template, is the most common technique currently in use to achieve spatial congruence across multiple subjects. This method corrects for global shape differences preserving regional asymmetries, but does not account for functional differences. We propose a novel approach to co-register task-based fMRI data using resting state group-ICA networks. We posit that these intrinsic networks (INs) can provide to the spatial normalization process with important information about how each individual's brain is organized functionally. The algorithm is initiated by the extraction of single subject representations of INs using group level independent component analysis (ICA) on resting state fMRI data. In this proof-of-concept work two of the robust, commonly identified, networks are chosen as functional templates. As an estimation step, the relevant INs are utilized to derive a set of normalization parameters for each subject. Finally, the normalization parameters are applied individually to a different set of fMRI data acquired while the subjects performed an auditory oddball task. These normalization parameters, although derived using rest data, generalize successfully to data obtained with a cognitive paradigm for each subject. The improvement in results is verified using two widely applied fMRI analysis methods: the general linear model and ICA. Resulting activation patterns from each analysis method show significant improvements in terms of detection sensitivity and statistical significance at the group level. The results presented in this article provide initial evidence to show that common functional domains from the resting state brain may be used to improve the group statistics of task-fMRI data.

A Demons algorithm for image registration with locally adaptive regularization.

Thirion's Demons is a popular algorithm for nonrigid image registration because of its linear computational complexity and ease of implementation. It approximately solves the diffusion registration problem by successively estimating force vectors that drive the deformation toward alignment and smoothing the force vectors by Gaussian convolution. In this article, we show how the Demons algorithm can be generalized to allow image-driven locally adaptive regularization in a manner that preserves both the linear complexity and ease of implementation of the original Demons algorithm. We show that the proposed algorithm exhibits lower target registration error and requires less computational effort than the original Demons algorithm on the registration of serial chest CT scans of patients with lung nodules.