@article {831, title = {Disruption of functional organization within the primary motor cortex in children with autism.}, journal = {Hum Brain Mapp}, volume = {35}, year = {2014}, month = {2014 Feb}, pages = {567-80}, abstract = {

Accumulating evidence suggests that motor impairments are prevalent in autism spectrum disorder (ASD), relate to the social and communicative deficits at the core of the diagnosis and may reflect abnormal connectivity within brain networks underlying motor control and learning. Parcellation of resting-state functional connectivity data using spectral clustering approaches has been shown to be an effective means of visualizing functional organization within the brain but has most commonly been applied to explorations of normal brain function. This article presents a parcellation of a key area of the motor network, the primary motor cortex (M1), a key area of the motor control network, in adults, typically developing (TD) children and children with ASD and introduces methods for selecting the number of parcels, matching parcels across groups and testing group differences. The parcellation is based solely on patterns of connectivity between individual M1 voxels and all voxels outside of M1, and within all groups, a gross dorsomedial to ventrolateral organization emerged within M1 which was left-right symmetric. Although this gross organizational scheme was present in both groups of children, statistically significant group differences in the size and segregation of M1 parcels within regions of the motor homunculus corresponding to the upper and lower limbs were observed. Qualitative comparison of the M1 parcellation for children with ASD with that of younger and older TD children suggests that these organizational differences, with a lack of differentiation between lower limb/trunk regions and upper limb/hand regions, may be due, at least in part, to a delay in functional specialization within the motor cortex.

}, keywords = {Adult, Autistic Disorder, brain mapping, Child, Developmental Disabilities, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Middle Aged, Motor Cortex, Oxygen, Young Adult}, issn = {1097-0193}, doi = {10.1002/hbm.22188}, author = {Nebel, Mary Beth and Joel, Suresh E and Muschelli, John and Barber, Anita D and Caffo, Brian S and Pekar, James J and Mostofsky, Stewart H} } @article {835, title = {Evaluating dynamic bivariate correlations in resting-state fMRI: a comparison study and a new approach.}, journal = {Neuroimage}, volume = {101}, year = {2014}, month = {2014 Nov 1}, pages = {531-46}, abstract = {

To date, most functional Magnetic Resonance Imaging (fMRI) studies have assumed that the functional connectivity (FC) between time series from distinct brain regions is constant across time. However, recently, there has been an increased interest in quantifying possible dynamic changes in FC during fMRI experiments, as it is thought that this may provide insight into the fundamental workings of brain networks. In this work we focus on the specific problem of estimating the dynamic behavior of pair-wise correlations between time courses extracted from two different regions of the brain. We critique the commonly used sliding-window technique, and discuss some alternative methods used to model volatility in the finance literature that could also prove to be useful in the neuroimaging setting. In particular, we focus on the Dynamic Conditional Correlation (DCC) model, which provides a model-based approach towards estimating dynamic correlations. We investigate the properties of several techniques in a series of simulation studies and find that DCC achieves the best overall balance between sensitivity and specificity in detecting dynamic changes in correlations. We also investigate its scalability beyond the bivariate case to demonstrate its utility for studying dynamic correlations between more than two brain regions. Finally, we illustrate its performance in an application to test-retest resting state fMRI data.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.06.052}, author = {Lindquist, Martin A and Xu, Yuting and Nebel, Mary Beth and Caffo, Brain S} } @article {790, title = {Health effects of lesion localization in multiple sclerosis: spatial registration and confounding adjustment.}, journal = {PLoS One}, volume = {9}, year = {2014}, month = {2014}, pages = {e107263}, abstract = {

Brain lesion localization in multiple sclerosis (MS) is thought to be associated with the type and severity of adverse health effects. However, several factors hinder statistical analyses of such associations using large MRI datasets: 1) spatial registration algorithms developed for healthy individuals may be less effective on diseased brains and lead to different spatial distributions of lesions; 2) interpretation of results requires the careful selection of confounders; and 3) most approaches have focused on voxel-wise regression approaches. In this paper, we evaluated the performance of five registration algorithms and observed that conclusions regarding lesion localization can vary substantially with the choice of registration algorithm. Methods for dealing with confounding factors due to differences in disease duration and local lesion volume are introduced. Voxel-wise regression is then extended by the introduction of a metric that measures the distance between a patient-specific lesion mask and the population prevalence map.

}, issn = {1932-6203}, doi = {10.1371/journal.pone.0107263}, author = {Eloyan, Ani and Shou, Haochang and Shinohara, Russell T and Sweeney, Elizabeth M and Nebel, Mary Beth and Cuzzocreo, Jennifer L and Calabresi, Peter A and Reich, Daniel S and Lindquist, Martin A and Crainiceanu, Ciprian M} } @article {818, title = {Reduction of motion-related artifacts in resting state fMRI using aCompCor.}, journal = {Neuroimage}, volume = {96}, year = {2014}, month = {2014 Aug 1}, pages = {22-35}, abstract = {

Recent studies have illustrated that motion-related artifacts remain in resting-state fMRI (rs-fMRI) data even after common corrective processing procedures have been applied, but the extent to which head motion distorts the data may be modulated by the corrective approach taken. We compare two different methods for estimating nuisance signals from tissues not expected to exhibit BOLD fMRI signals of neuronal origin: 1) the more commonly used mean signal method and 2) the principal components analysis approach (aCompCor: Behzadi et al., 2007). Further, we investigate the added benefit of "scrubbing" (Power et al., 2012) following both methods. We demonstrate that the use of aCompCor removes motion artifacts more effectively than tissue-mean signal regression. In addition, inclusion of more components from anatomically defined regions of no interest better mitigates motion-related artifacts and improves the specificity of functional connectivity estimates. While scrubbing further attenuates motion-related artifacts when mean signals are used, scrubbing provides no additional benefit in terms of motion artifact reduction or connectivity specificity when using aCompCor.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.03.028}, author = {Muschelli, John and Nebel, Mary Beth and Caffo, Brian S and Barber, Anita D and Pekar, James J and Mostofsky, Stewart H} } @article {792, title = {Shrinkage prediction of seed-voxel brain connectivity using resting state fMRI.}, journal = {Neuroimage}, volume = {102 Pt 2}, year = {2014}, month = {2014 Nov 15}, pages = {938-44}, abstract = {

Resting-state functional magnetic resonance imaging (rs-fMRI) is used to investigate synchronous activations in spatially distinct regions of the brain, which are thought to reflect functional systems supporting cognitive processes. Analyses are often performed using seed-based correlation analysis, allowing researchers to explore functional connectivity between data in a seed region and the rest of the brain. Using scan-rescan rs-fMRI data, we investigate how well the subject-specific seed-based correlation map from the second replication of the study can be predicted using data from the first replication. We show that one can dramatically improve prediction of subject-specific connectivity by borrowing strength from the group correlation map computed using all other subjects in the study. Even more surprisingly, we found that the group correlation map provided a better prediction of a subject{\textquoteright}s connectivity than the individual{\textquoteright}s own data. While further discussion and experimentation are required to understand how this can be used in practice, results indicate that shrinkage-based methods that borrow strength from the population mean should play a role in rs-fMRI data analysis.

}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2014.05.043}, author = {Shou, Haochang and Eloyan, Ani and Nebel, Mary Beth and Mejia, Amanda and Pekar, James J and Mostofsky, Stewart and Caffo, Brian and Lindquist, Martin A and Crainiceanu, Ciprian M} } @article {799, title = {Body composition and arsenic metabolism: a cross-sectional analysis in the Strong Heart Study.}, journal = {Environ Health}, volume = {12}, year = {2013}, month = {2013}, pages = {107}, abstract = {

OBJECTIVE: The objective of this study was to evaluate the association between measures of body composition and patterns of urine arsenic metabolites in the 1989-1991 baseline visit of the Strong Heart Study, a cardiovascular disease cohort of adults recruited from rural communities in Arizona, Oklahoma, North Dakota and South Dakota.

METHODS: We evaluated 3,663 Strong Heart Study participants with urine arsenic species above the limit of detection and no missing data on body mass index, \% body fat and fat free mass measured by bioelectrical impedance, waist circumference and other variables. We summarized urine arsenic species patterns as the relative contribution of inorganic (iAs), methylarsonate (MMA) and dimethylarsinate (DMA) species to their sum. We modeled the associations of \% arsenic species biomarkers with body mass index, \% body fat, fat free mass, and waist circumference categories in unadjusted regression models and in models including all measures of body composition. We also considered adjustment for arsenic exposure and demographics.

RESULTS: Increasing body mass index was associated with higher mean \% DMA and lower mean \% MMA before and after adjustment for sociodemographic variables, arsenic exposure, and for other measures of body composition. In unadjusted linear regression models, \% DMA was 2.4 (2.1, 2.6) \% higher per increase in body mass index category (< 25, >=25 \& <30, >=30 \& <35, >=35 kg/m2), and \% MMA was 1.6 (1.4, 1.7) \% lower. Similar patterns were observed for \% body fat, fat free mass, and waist circumference measures in unadjusted models and in models adjusted for potential confounders, but the associations were largely attenuated or disappeared when adjusted for body mass index.

CONCLUSION: Measures of body size, especially body mass index, are associated with arsenic metabolism biomarkers. The association may be related to adiposity, fat free mass or body size. Future epidemiologic studies of arsenic should consider body mass index as a potential modifier for arsenic-related health effects.

}, issn = {1476-069X}, doi = {10.1186/1476-069X-12-107}, author = {Gribble, Matthew O and Crainiceanu, Ciprian M and Howard, Barbara V and Umans, Jason G and Francesconi, Kevin A and Goessler, Walter and Zhang, Ying and Silbergeld, Ellen K and Guallar, Eliseo and Navas-Acien, Ana} } @article {809, title = {In vivo identification of morphologic retinal abnormalities in neuromyelitis optica.}, journal = {Neurology}, volume = {80}, year = {2013}, month = {2013 Apr 9}, pages = {1406-14}, abstract = {

OBJECTIVE: To assess eyes with neuromyelitis optica (NMO) for morphologic retinal abnormalities utilizing high-definition optical coherence tomography (OCT) imaging.

METHODS: In this cross-sectional study, 39 patients with NMO spectrum disorders and 39 age- and sex-matched healthy controls underwent spectral-domain OCT and visual function testing.

RESULTS: Microcystic macular edema (MME) of the inner nuclear layer (INL) was identified in 10 of 39 patients (26\%) and was exclusively found in eyes with a history of optic neuritis (ON). MME eyes had lower high- and low-contrast letter-acuity scores (100\%: p = 0.002; 2.5\%: p = 0.002; 1.25\%: p = 0.004), lower peripapillary retinal nerve fiber layer (RNFL) thickness (p = 0.04), lower macular RNFL thickness (p = 0.004), lower ganglion cell layer + inner plexiform layer (GCIP) thickness (p = 0.007), higher INL thickness (p < 0.001), and a greater number of ON episodes (p = 0.008) relative to non-MME eyes with a history of ON. After adjusting for history of multiple ON episodes, these findings remained significant for macular-RNFL thickness (p = 0.03), INL thickness (p < 0.001), and 100\% and 2.5\% contrast letter-acuity scores (p = 0.008 and p = 0.03, respectively). NMO spectrum eyes without ON history had lower macular RNFL thickness (p = 0.003), GCIP thickness (p = 0.002), outer nuclear layer thickness (p = 0.02), and low-contrast letter-acuity scores (2.5\%: p = 0.03; 1.25\%: p = 0.002) compared to healthy controls.

CONCLUSIONS: We have identified a pattern of retinal morphologic abnormalities in NMO that is associated with severe retinal axonal and neuronal loss and corresponding visual disability. MME may contribute to poor visual outcomes following NMO-associated ON or alternatively represent a marker of ON severity. Additionally, our results support that subclinical involvement of the anterior visual pathway may occur in NMO spectrum disorders.

}, keywords = {Adolescent, Adult, Aged, Aquaporin 4, Autoantibodies, Case-Control Studies, Chi-Square Distribution, Female, Humans, Macular Edema, Male, Middle Aged, Nerve Fibers, Neuromyelitis Optica, Retina, Tomography, Optical Coherence, Vision Tests, Visual Acuity, Young Adult}, issn = {1526-632X}, doi = {10.1212/WNL.0b013e31828c2f7a}, author = {Sotirchos, Elias S and Saidha, Shiv and Byraiah, Gita and Mealy, Maureen A and Ibrahim, Mohamed A and Sepah, Yasir Jamal and Newsome, Scott D and Ratchford, John N and Frohman, Elliot M and Balcer, Laura J and Crainiceanu, Ciprian M and Nguyen, Quan Dong and Levy, Michael and Calabresi, Peter A} } @article {801, title = {Quantification of multiple-sclerosis-related brain atrophy in two heterogeneous MRI datasets using mixed-effects modeling.}, journal = {Neuroimage Clin}, volume = {3}, year = {2013}, month = {2013}, pages = {171-9}, abstract = {

Brain atrophy, measured by MRI, has been proposed as a useful surrogate marker for disease progression in multiple sclerosis (MS). However, it is conventionally assumed that the accurate quantification of brain atrophy is made difficult, if not impossible, by changes in the parameters of the MRI acquisition, which are almost inevitable over the course of a longitudinal study since MRI technology changes rapidly. This state of affairs can negatively affect clinical trial design and limit the use of historical data. Here, we investigate whether we can coherently estimate brain atrophy rates in a heterogeneous MS sample via linear mixed-effects multivariable regression, incorporating three critical assumptions: (1) using age at time of scanning, rather than time since baseline, as the regressor of interest; (2) scanning individuals with a variety of techniques; and (3) introducing a simple additive correction for major differences in MRI protocol. We fit the model to several measures of brain volume as the outcome in two MS populations: 1123 scans from 195 cases acquired for over approximately 7~years in two natural history protocols (Cohort 1), and 1331 scans from 69 cases seen for over 11~years who were primarily treated with two specific MS disease-modifying therapies (Cohort 2). We compared the mixed-effects model with additive correction for MRI acquisition parameters to a model fit without this correction and performed sample-size calculations to provide an estimate of the number of participants in an MS clinical trial that might be required to see a therapeutic effect of treatment using the approach described here. The results show that without the additive correction for T1-weighted protocol parameters, atrophy was underestimated and subject-specific estimates were more narrowly distributed about the population mean. Ventricular CSF is the most consistently estimated brain volume, with a mean of 2.8\%/year increase in Cohort 1 and 4.4\%/year increase in Cohort 2. An interesting observation was that gray matter volume decreased and white matter volume remained essentially unchanged in both cohorts, suggesting that changes in ventricular CSF volume are a surrogate for changes in gray matter volume. In conclusion, the mixed-effects modeling framework presented here allows effective use of heterogeneously acquired and historical data in the study of brain atrophy in MS, potentially simplifying the design of future single- and multi-site clinical trials and natural history studies.

}, issn = {2213-1582}, doi = {10.1016/j.nicl.2013.08.001}, author = {Jones, Blake C and Nair, Govind and Shea, Colin D and Crainiceanu, Ciprian M and Cortese, Irene C M and Reich, Daniel S} } @article {803, title = {Quantifying the reliability of image replication studies: the image intraclass correlation coefficient (I2C2).}, journal = {Cogn Affect Behav Neurosci}, volume = {13}, year = {2013}, month = {2013 Dec}, pages = {714-24}, abstract = {

This article proposes the image intraclass correlation (I2C2) coefficient as a global measure of reliability for imaging studies. The I2C2 generalizes the classic intraclass correlation (ICC) coefficient to the case when the data of interest are images, thereby providing a measure that is both intuitive and convenient. Drawing a connection with classical measurement error models for replication experiments, the I2C2 can be computed quickly, even in high-dimensional imaging studies. A nonparametric bootstrap procedure is introduced to quantify the variability of the I2C2 estimator. Furthermore, a Monte Carlo permutation is utilized to test reproducibility versus a zero I2C2, representing complete lack of reproducibility. Methodologies are applied to three replication studies arising from different brain imaging modalities and settings: regional analysis of volumes in normalized space imaging for characterizing brain morphology, seed-voxel brain activation maps based on resting-state functional magnetic resonance imaging (fMRI), and fractional anisotropy in an area surrounding the corpus callosum via diffusion tensor imaging. Notably, resting-state fMRI brain activation maps are found to have low reliability, ranging from .2 to .4. Software and data are available to provide easy access to the proposed methods.

}, keywords = {Adult, Brain, brain mapping, Computer Simulation, Female, Humans, Male, Models, Biological, Neuroimaging, Reproducibility of Results, Statistics as Topic}, issn = {1531-135X}, doi = {10.3758/s13415-013-0196-0}, author = {Shou, H and Eloyan, A and Lee, S and Zipunnikov, V and Crainiceanu, A N and Nebel, N B and Caffo, B and Lindquist, M A and Crainiceanu, C M} } @article {811, title = {Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Jan}, pages = {34-43}, abstract = {

OBJECTIVE: To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS).

DESIGN: Cross-sectional study.

SETTING: Johns Hopkins University, Baltimore, Maryland.

PARTICIPANTS: A total of 84 patients with MS and 24 healthy control subjects.

MAIN OUTCOME MEASURES: High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes.

RESULTS: Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer+inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P=.01 and P=.04, respectively) and caudate (P=.04 and P=.03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P=.007) and inversely associated with normal-appearing white matter volume (P=.005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

}, keywords = {Adult, Axons, Caudate Nucleus, Central Nervous System, Cerebral Cortex, Cross-Sectional Studies, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Retina, Retinal Neurons, Tomography, Optical Coherence}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.573}, author = {Saidha, Shiv and Sotirchos, Elias S and Oh, Jiwon and Syc, Stephanie B and Seigo, Michaela A and Shiee, Navid and Eckstein, Chistopher and Durbin, Mary K and Oakley, Jonathan D and Meyer, Scott A and Frohman, Teresa C and Newsome, Scott and Ratchford, John N and Balcer, Laura J and Pham, Dzung L and Crainiceanu, Ciprian M and Frohman, Elliot M and Reich, Daniel S and Calabresi, Peter A} } @article {708, title = {Arsenic exposure, diabetes prevalence, and diabetes control in the Strong Heart Study.}, journal = {Am J Epidemiol}, volume = {176}, year = {2012}, month = {2012 Nov 15}, pages = {865-74}, abstract = {

This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, Oklahoma, and North and South Dakota (1989-1991). We studied 3,925 men and women 45-74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5\% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 {\textmu}g/L (interquartile range, 7.9-24.2). Diabetes prevalence was 49.4\%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95\% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c >=8\%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed.

}, keywords = {Aged, Arizona, Arsenicals, Blood Glucose, Creatinine, Diabetes Mellitus, Environmental Exposure, Female, Hemoglobin A, Glycosylated, Humans, Indians, North American, Male, Middle Aged, North Dakota, Oklahoma, Poisson Distribution, Prevalence, Regression Analysis, Risk Factors, South Dakota}, issn = {1476-6256}, doi = {10.1093/aje/kws153}, author = {Gribble, Matthew O and Howard, Barbara V and Umans, Jason G and Shara, Nawar M and Francesconi, Kevin A and Goessler, Walter and Crainiceanu, Ciprian M and Silbergeld, Ellen K and Guallar, Eliseo and Navas-Acien, Ana} } @article {pmid22472185, title = {Cadmium Exposure and All Cause and Cardiovascular Mortality in the US General Population}, journal = {Environ Health Perspect}, year = {2012}, month = {Apr}, author = {Tellez-Plaza, M. and Navas-Acien, A. and Menke, A. and Crainiceanu, C and Pastor-Barriuso, R. and Guallar, E.} } @article {nicole, title = {Distribution of cell-free and cell-associated HIV surrogates in the female genital tract following simulated vaginal intercourse}, journal = {Appeared online in the Journal of Infectious Diseases}, year = {2012}, author = {Louissaint, N and Nimmagadda, S and Bakshi, R and Du, Y and Macura, K and King, K and Wahl, R and Goldsmith, J and Caffo, B and Cao, Y and Anderson, J and Fuchs, E and Hendrix, C} } @article {709, title = {Microcystic macular oedema, thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study.}, journal = {Lancet Neurol}, volume = {11}, year = {2012}, month = {2012 Nov}, pages = {963-72}, abstract = {

BACKGROUND: Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression.

METHODS: This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters.

FINDINGS: 164 patients with MS and 60 healthy controls were assessed. Mean follow-up was 25{\textperiodcentered}8 months (SD 9{\textperiodcentered}1) for patients with MS and 22{\textperiodcentered}4 months (11{\textperiodcentered}4) for healthy controls. Ten (6\%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5{\textperiodcentered}93 [range 2{\textperiodcentered}44-8{\textperiodcentered}91]) than those who did not have MMO at any time during the study (151 patients; 3{\textperiodcentered}81 [0{\textperiodcentered}13-9{\textperiodcentered}47]; p=0{\textperiodcentered}032), although expanded disability status scale (EDSS) scores were not significantly different (5{\textperiodcentered}2 [1{\textperiodcentered}0-6{\textperiodcentered}5] for patients with MS and MMO vs 2{\textperiodcentered}5 [0{\textperiodcentered}0-8{\textperiodcentered}0] for those without MMO; p=0{\textperiodcentered}097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100\% contrast, p=0{\textperiodcentered}017; 2{\textperiodcentered}5\% contrast, p=0{\textperiodcentered}031; 1{\textperiodcentered}25\% contrast, p=0{\textperiodcentered}014), and increased INL thicknesses (p=0{\textperiodcentered}003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0{\textperiodcentered}007), new T2 lesions (p=0{\textperiodcentered}015), EDSS progression (p=0{\textperiodcentered}034), and relapses in patients with relapsing-remitting MS (p=0{\textperiodcentered}008) during the study. MMO was not associated with disease activity during follow-up.

INTERPRETATION: Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS.

FUNDING: National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.

}, keywords = {Adult, Cohort Studies, Female, Follow-Up Studies, Humans, Macular Edema, Male, Middle Aged, Multiple Sclerosis, Retina, Retinal Ganglion Cells, Retrospective Studies, Tomography, Optical Coherence}, issn = {1474-4465}, doi = {10.1016/S1474-4422(12)70213-2}, author = {Saidha, Shiv and Sotirchos, Elias S and Ibrahim, Mohamed A and Crainiceanu, Ciprian M and Gelfand, Jeffrey M and Sepah, Yasir J and Ratchford, John N and Oh, Jiwon and Seigo, Michaela A and Newsome, Scott D and Balcer, Laura J and Frohman, Elliot M and Green, Ari J and Nguyen, Quan D and Calabresi, Peter A} } @article {pmid22006982, title = {Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis}, journal = {Brain}, volume = {135}, number = {Pt 2}, year = {2012}, month = {Feb}, pages = {521{\textendash}533}, author = {Syc, S. B. and Saidha, S. and Newsome, S and Ratchford, J and Levy, M. and Ford, E. and Crainiceanu, C and Durbin, M. K. and Oakley, J. D. and Meyer, S. A. and Frohman, E. M. and Calabresi, P} } @article {710, title = {Relationships Between Retinal Axonal and Neuronal Measures and Global Central Nervous System Pathology in Multiple Sclerosis.}, journal = {Arch Neurol}, year = {2012}, month = {2012 Oct 1}, pages = {1-10}, abstract = {

OBJECTIVE To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS). DESIGN Cross-sectional study. SETTING Johns Hopkins University, Baltimore, Maryland. PARTICIPANTS A total of 84 patients with MS and 24 healthy control subjects. MAIN OUTCOME MEASURES High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes. RESULTS Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer\ +\ inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P\ =\ .01 and P\ =\ .04, respectively) and caudate (P\ =\ .04 and P\ =\ .03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P\ =\ .007) and inversely associated with normal-appearing white matter volume (P\ =\ .005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

}, issn = {1538-3687}, doi = {10.1001/archneurol.2013.573}, author = {Saidha, Shiv and Sotirchos, Elias S and Oh, Jiwon and Syc, Stephanie B and Seigo, Michaela A and Shiee, Navid and Eckstein, Chistopher and Durbin, Mary K and Oakley, Jonathan D and Meyer, Scott A and Frohman, Teresa C and Newsome, Scott and Ratchford, John N and Balcer, Laura J and Pham, Dzung L and Crainiceanu, Ciprian M and Frohman, Elliot M and Reich, Daniel S and Calabresi, Peter A} } @article {shee, title = {Revisiting Brain Atrophy and Its Relationship to Disability in Multiple Sclerosis}, journal = {PLoS ONE}, volume = {7}, number = {5}, year = {2012}, month = {05}, pages = {e37049}, publisher = {Public Library of Science}, doi = {10.1371/journal.pone.0037049}, url = {http://dx.doi.org/10.1371\%2Fjournal.pone.0037049}, author = {Shiee, N and Bazin, P and Zackowski, K and Farrell, S and Harrison, D and Newsome, S and Ratchford, J and Caffo, B and Calabresi, P and Pham, D and Reich, D.} } @article {PACE:PACE2905, title = {Clinical predictors of conduction disease progression in type I myotonic muscular dystrophy}, journal = {Pacing and Clinical Electrophysiology, PMCID: PMC3035751}, volume = {34}, number = {2}, year = {2011}, pages = {171{\textendash}176}, publisher = {Blackwell Publishing Inc}, keywords = {cardiomyopathy, conduction disease, electrocardiography, myotonic muscular dystrophy, sudden death}, issn = {1540-8159}, doi = {10.1111/j.1540-8159.2010.02905.x}, url = {http://dx.doi.org/10.1111/j.1540-8159.2010.02905.x}, author = {Nazarian, S and Wagner, K and Caffo, B and Tomaselli, G} } @article {nicole2, title = {Distribution of Cell-free and Cell-associated HIV surrogates in the Colon Following Simulated Receptive Anal Intercourse in Healthy Men}, journal = {Journal of Acquired Immune Defficiency Syndromes, Basic and Translational Science}, volume = {59}, number = {1}, year = {2011}, pages = {10{\textendash}17}, author = {Louissaint, N and Nimmagadda, S and Fuchs, E and Bashki, R and Cao, Y and Lee, L and Goldsmith, J and Caffo, B and Du, Y and King, K and Menendez, F and Torbenson, M and Hendrix, C} } @article {nazarian2011AI, title = {Prospective study to assess the safety of a protocol for magnetic resonance imaging of patients with implanted cardiac devices}, journal = {Annals of Interal Medicine}, volume = {155}, number = {7}, year = {2011}, pages = {415{\textendash}424}, publisher = {American College of Physicians}, author = {Nazarian, S and Hansford, R and Roguin, A and Goldsher, D and Zviman, M and Lardo, A and Caffo, B and Frick, K and Kraut, M and Kamel, I and Ihab, R and Calkins, H and Berger, R and Bluemke, D and Halperin, H} } @article {pmid20693268, title = {Cadmium and peripheral arterial disease: gender differences in the 1999-2004 US National Health and Nutrition Examination Survey}, journal = {Am. J. Epidemiol.}, volume = {172}, number = {6}, year = {2010}, month = {Sep}, pages = {671{\textendash}681}, author = {Tellez-Plaza, M. and Navas-Acien, A. and Crainiceanu, C and Sharrett, A. R. and Guallar, E.} } @article {kriegeskorte2010everything, title = {Everything you never wanted to know about circular analysis, but were afraid to ask}, journal = {Journal of Cerebral Blood Flow \& Metabolism}, volume = {30}, number = {9}, year = {2010}, pages = {1551{\textendash}1557}, publisher = {Nature Publishing Group}, author = {Kriegeskorte, Nikolaus and Lindquist, Martin A and Nichols, Thomas E and Poldrack, Russell A and Vul, Edward} } @article {847, title = {Everything you never wanted to know about circular analysis, but were afraid to ask.}, journal = {J Cereb Blood Flow Metab}, volume = {30}, year = {2010}, month = {2010 Sep}, pages = {1551-7}, abstract = {

Over the past year, a heated discussion about {\textquoteright}circular{\textquoteright} or {\textquoteright}nonindependent{\textquoteright} analysis in brain imaging has emerged in the literature. An analysis is circular (or nonindependent) if it is based on data that were selected for showing the effect of interest or a related effect. The authors of this paper are researchers who have contributed to the discussion and span a range of viewpoints. To clarify points of agreement and disagreement in the community, we collaboratively assembled a series of questions on circularity herein, to which we provide our individual current answers in }, keywords = {Brain, brain mapping, Data Interpretation, Statistical, Guidelines as Topic, Image Processing, Computer-Assisted, Neurosciences, Publications, Research Design, Selection Bias}, issn = {1559-7016}, doi = {10.1038/jcbfm.2010.86}, author = {Kriegeskorte, Nikolaus and Lindquist, Martin A and Nichols, Thomas E and Poldrack, Russell A and Vul, Edward} } @article {nazarian:qrs, title = {QRS Prolongation in Myotonic Muscular Dystrophy and Diffuse Fibrosis on Cardiac Magnetic Resonance}, journal = {Magnetic Resonance in Medicine, PMCID: PMC3034129}, volume = {64}, number = {1}, year = {2010}, pages = {107{\textendash}114}, author = {Nazarian, S and Bluemke, D and Wagner, K and Zviman, M and Turkbey, E and Caffo, B and Shehata, M and Edwards,D and Butcher, B and Calkins, H and Berger, R and Halperin, H and Tomaselli, G} } @article {Wager09a, title = {Brain mediators of cardiovascular responses to social threat, Part I: Reciprocal dorsal and ventral sub-regions of the medial prefrontal cortex and heart-rate reactivity}, journal = {NeuroImage}, volume = {47}, year = {2009}, pages = {821-835}, author = {Wager, T.D. and Waugh, C.E. and Lindquist, Martin A and Noll, D.C. and Fredrickson, B.L. and Taylor, S.F.} } @article {wager2009evaluating, title = {Evaluating the consistency and specificity of neuroimaging data using meta-analysis}, journal = {Neuroimage}, volume = {45}, number = {1}, year = {2009}, pages = {S210{\textendash}S221}, publisher = {Elsevier}, author = {Wager, Tor D and Lindquist, Martin A and Nichols, Thomas E and Kober, Hedy and Van Snellenberg, Jared X} } @article {pmid20049214, title = {Mercury induces an unopposed inflammatory response in human peripheral blood mononuclear cells in vitro}, journal = {Environ. Health Perspect.}, volume = {117}, number = {12}, year = {2009}, month = {Dec}, pages = {1932{\textendash}1938}, author = {Gardner, R. M. and Nyland, J. F. and Evans, S. L. and Wang, S. B. and Doyle, K. M. and Crainiceanu, C and Silbergeld, E. K.} } @article {o2009prospective, title = {Prospective Study of Sleep-disordered Breathing and Hypertension: The Sleep Heart Health Study}, journal = {American Journal of Respiratory and Critical Care Medicine, PMCID: PMC2695498}, volume = {179}, number = {12}, year = {2009}, pages = {1159{\textendash}1164}, publisher = {Am Thoracic Soc}, author = {O{\textquoteright}Connor, G and Caffo, B and Newman, A and Quan, S and Rapoport, D and Redline, S and Resnick, H and Samet, J and Shahar, E} } @article {punjabi, title = {Sleep-disordered Breathing and Mortality: a Prospective Cohort Study}, journal = {PLOS Medicine, PMCID: PMC2722083}, volume = {6}, year = {2009}, author = {Punjabi, N and Caffo, B and Goodwin, J and Gottlieb, D and Newman, A and O{\textquoteright}Connor, G and Rapoport, D and Redline, S and Resnick, H and Robbins, J and Samet, J and Shahar, E and Unruh, M} } @article {pmid19750109, title = {Urine arsenic concentrations and species excretion patterns in American Indian communities over a 10-year period: the Strong Heart Study}, journal = {Environ. Health Perspect.}, volume = {117}, number = {9}, year = {2009}, month = {Sep}, pages = {1428{\textendash}1433}, author = {Navas-Acien, A. and Umans, J. G. and Howard, B. V. and Goessler, W. and Francesconi, K. A. and Crainiceanu, C and Silbergeld, E. K. and Guallar, E.} } @article {pmid18197299, title = {Cadmium exposure and hypertension in the 1999-2004 National Health and Nutrition Examination Survey (NHANES)}, journal = {Environ. Health Perspect.}, volume = {116}, number = {1}, year = {2008}, month = {Jan}, pages = {51{\textendash}56}, author = {Tellez-Plaza, M. and Navas-Acien, A. and Crainiceanu, C and Guallar, E.} } @article {choi2008mechanistic, title = {A mechanistic latent variable model for estimating drug concentrations in the male genital tract: A case study in drug kinetics}, journal = {Statistics in Medicine, PMCID: PMC2763330}, volume = {27}, number = {14}, year = {2008}, pages = {2697{\textendash}2714}, publisher = {John Wiley \& Sons, Ltd Chichester, UK}, author = {Choi, L and Caffo, B and Rohde, C and Ndovi, T and Hendrix, C} } @article {cao2007effect, title = {Effect of semen sampling frequency on seminal antiretroviral drug concentration}, journal = {Clinical Pharmacology \& Therapeutics}, volume = {83}, number = {6}, year = {2007}, pages = {848{\textendash}856}, publisher = {Nature Publishing Group}, author = {Cao, Y and Ndovi, T and Parsons, T and Guidos, A and Caffo, B and Hendrix, C} } @article {ndovi2007new, title = {A new method to estimate quantitatively seminal vesicle and prostate gland contributions to ejaculate}, journal = {British Journal of Clinical Pharmacology, PMCID: PMC2203235}, volume = {63}, number = {4}, year = {2007}, pages = {404-420}, publisher = {Blackwell Publishing}, author = {Ndovi, T and Parsons, T and Choi, L and Caffo, B and Rohde, C and Hendrix, C} } @article {jones2006fixed, title = {Fixed-width output analysis for Markov chain Monte Carlo}, journal = {Journal of the American Statistical Association}, volume = {101}, number = {476}, year = {2006}, pages = {1537{\textendash}1547}, publisher = {ASA}, author = {Jones, G and Haran, M and Caffo, B and Neath, R} } @article {ndovi2006quantitative, title = {Quantitative assessment of seminal vesicle and prostate drug concentrations by use of a noninvasive method}, journal = {Clinical Pharmacology \& Therapeutics}, volume = {80}, number = {2}, year = {2006}, pages = {146{\textendash}158}, publisher = {Nature Publishing Group}, author = {Ndovi, T and Choi, L and Caffo, B and Parsons, T and Baker, S and Zhao, M and Rohde, C and Hendrix, C} }